2,4,5-trisubstituted 1,2,4-triazolones useful as inhibitors of DHODH

ABSTRACT

The present invention provides triazolone compounds of general formula (I):in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

This application is a continuation of U.S. patent application Ser. No.16/345,168, which was filed on Apr. 25, 2019, now issued as U.S. Pat.No. 10,815,215, which is the U.S. national phase application pursuant to35 U.S.C. § 371 of PCT International Application Serial No.PCT/EP2017/077252, filed Oct. 25, 2017, which claims priority to and thebenefit of PCT Patent Application No. PCT/CN2016/103643, filed Oct. 27,2016, and which claims benefit of U.S. Provisional Application No.62/569,296, filed Oct. 6, 2017. The entire contents of each of which areincorporated herein by reference.

The present invention provides 2,4,5-trisubstituted 1,2,4-triazolonecompounds of general formula (I) as described and defined herein,methods of preparing said compounds, intermediate compounds useful forpreparing said compounds, pharmaceutical compositions and combinationscomprising said compounds, and the use of said compounds formanufacturing pharmaceutical compositions for the treatment orprophylaxis of diseases, in particular of hyperproliferative and/orinflammatory disorders, as a sole agent or in combination with otheractive ingredients.

BACKGROUND

The present invention provides 2,4,5-trisubstituted 1,2,4-triazolonecompounds of general formula (I) which inhibit DihydroorotateDehydrogenase (DHODH).

Acute myeloid leukemia (AML) is the most common acute leukemia in humanswith a 5 year survival of only about 30%. AML is a malignancy of themyeloid line of blood cells. The incidence rates and chances of cure arehighly age dependent. The chemotherapy standard of care for AML has notchanged significantly over the last decades highlighting the need fornovel therapies. A major hallmark of AML is differentiation arrest ofthe leukemic cells at early stages of cellular differentiation. Thepotential of leukemic differentiation therapy can be seen with thesuccess of ATRA or arsenic trioxide inducing differentiation in acutepromyelocytic leukemia (APL). Around 10% of AML belong to the APLsubtype where leukemic cells are harbouring a chromosomal translocationresulting in fusions of oncoproteins involving the retinoic acidreceptor. While treatment with ATRA or arsenic trioxide leads to adramatic increase of patient survival, with overall survival rates ofover 70%, unfortunately a comparable differentiation therapy for thenon-APL AMLs is lacking (Management of acute promyelocytic leukemia:recommendations from an expert panel on behalf of the EuropeanLeukemiaNet, Sanz M. A. et al, Blood 2009, 113(9), 1875-1891). Thereforenew therapies inducing differentiation of AML cells are of high interestand medical need.

Dihydroorotate Dehydrogenase (DHODH)

DHODH is located in the mitochondria and the enzyme responsible for the4^(th) and rate limiting step in de novo pyrimidine synthesis convertingdihydroorotate to orotate (Dihydroorotat-ubiquinone oxidoreductase linksmitochondria in the biosynthesis of pyrimidine nucleotides, Löffler M.et al, Molecular and Cellular Biochemistry 1997, 174, 125-129).

As pyrimdine production is essential for DNA and RNA synthesis DHODH ishighly important for cellular proliferation. The enzyme is considered anattractive drug target for cancer, immunological, parasitic and viraldiseases and DHODH small molecule inhibitors likeLeflunomide/Teriflunomide and Brequinar have been approved for clinicaluse in Rheumatoid Arthritis and Multiple Sclerosis. Additionally,preclinical studies indicate that DHODH inhibitors may be useful for thetreatment of haematological cancer indications, for the treatment ofsolid tumors (e.g., neuroblastoma, melanoma, colon, breast and lungtumors), for the treatment of parasitic diseases (e.g., malaria), andfor viral disease therapy.

U.S. Pat. No. 6,444,613 B1 relates to the field of defoliants, inparticular thidiazuron-comprising mixtures, and their use in crops ofcotton. These mixtures comprise among others 2,4,5-trisubstituted1,2,4-triazolone compounds as herbicides, which inhibit the enzymeprotoporphyrinogen-(IX) oxidase (PPO inhibitors).

WO199802422 describes substituted aromatic carbonyl compounds, amongothers 2,4,5-trisubstituted 1,2,4-triazolone compounds, as herbicides.

From CN106543139 some triazolone compounds are known as agrochemicals.

US 2016/0251341 A1 describes triazole compounds as serine proteaseinhibitors useful for the inhibition of thrombin and/or kallikrein.

WO2010/077686 A1 describes sirtuin-modulating compounds, e.g.isoindolinone and related compounds, and methods of use thereof. Thesirtuin-modulating compounds may be used for increasing the lifespan ofa cell, and treating and/or preventing a wide variety of diseases anddisorders including, for example, diseases or disorders related to agingor stress, diabetes, obesity, neurodegenerative diseases, cardiovasculardisease, blood clotting disorders, inflammation, cancer, and/or flushingas well as diseases or disorders that would benefit from increasedmitochondrial activity.

WO 2013/186692 A1 describes triazolone compounds as mPGES-1 inhibitors,useful in the treatment of pain and/or inflammation from a variety ofdiseases or conditions, such as asthma, osteoarthritis, rheumatoidarthritis, acute or chronic pain and neurodegenerative diseases.

However, the state of the art does not describe the specific2,4,5-trisubstituted 1,2,4-triazolone compounds of general formula (I)of the present invention as described and defined herein.

DESCRIPTION

It has now been found, and this partially constitutes the basis of thepresent invention, that the compounds of the present invention (e.g. thecompounds of general formula (I)) have surprising and advantageousproperties.

In particular, the compounds of the present invention have surprisinglybeen found to effectively inhibit DHODH and may therefore be used forthe treatment or prophylaxis of hyperproliferative and/or inflammatorydisorders, such as cancer, for example.

In accordance with one aspect, the present invention provides compoundsof general formula (I)

in which

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from hydroxy, phenyl and —N(R⁷)(R⁸),            -   and wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy                and hydroxy,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group, a C₃-C₈-heterocycloalkyl group, or a phenyl group    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group,        -   wherein said 4-7-membered heterocycloalkyl group and said 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom, and which is            optionally substituted one or two times, each substituent            independently selected from a group selected from            C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), hydroxy, cyano, C₁-C₆-hydroxyalkyl,            C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₆-alkyl)-, —SH, —S—(C₁-C₆-alkyl),            —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂,            —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or        -   wherein two vicinal substituents may form together a 5- or            6-membered, optionally heterocyclic, aromatic or            non-aromatic ring, having optionally 1-3 heteroatoms            independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,            and optionally containing a C(═O) group, and wherein the so            formed ring is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)    -   a bicyclic aryl group,    -   a partially saturated mono- or bicyclic aryl- or heteroaryl        group, and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and            —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a C₃-C₈-cycloalkyl            group or a NR⁷R⁸ group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group,    -   a C₂-C₆-alkenyl group,    -   a C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group,    -   a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group and which is            optionally substituted with a C₁-C₃-alkyl group, and    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁴ represents a group selected from,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,                aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,                —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),                S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂,                and —N(R⁷)(R⁸)    -   a C₂-C₆-alkenyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₂-C₆-haloalkyl group,    -   a C₂-C₆-hydroxyalkyl group,    -   a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)NR⁷R⁸ group, and    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₁-C₆-alkyl)-O—(C₁-C₆-alkyl) group,    -   a C₂-C₆-alkenyl group,    -   a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group, and    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group,    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group, and    -   a phenyl group        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        C₃-C₆-cycloalkyl group, and a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,    -   which is optionally substituted with a group selected from    -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxid thereof.

DETAILED DESCRIPTION Definitions

The term “substituted” means that one or more hydrogen atoms on thedesignated atom or group are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded. Combinations ofsubstituents and/or variables are permissible.

The term “optionally substituted” means that the number of substituentscan be equal to or different from zero. Unless otherwise indicated, itis possible that optionally substituted groups are substituted with asmany optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbon ornitrogen atom. Commonly, it is possible for the number of optionalsubstituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or3.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of general formula (I) of the presentinvention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, moreparticularly 1, 2 or 3, even more particularly 1 or 2”.

As used herein, an oxo substituent represents an oxygen atom, which isbound to a carbon atom or to a sulfur atom via a double bond.

The term “ring substituent” means a substituent attached to an aromaticor nonaromatic ring which replaces an available hydrogen atom on thering.

Should a composite substituent be composed of more than one parts, e.g.(C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, it is possible for the position of agiven part to be at any suitable position of said composite substituent,i.e. the C₁-C₃-alkoxy part can be attached to any carbon atom of theC₁-C₆-alkyl part of said (C₁-C₃-alkoxy)-(C₁-C₆alkyl)- group. A hyphen atthe beginning or at the end of such a composite substituent indicatesthe point of attachment of said composite substituent to the rest of themolecule. Should a ring, comprising carbon atoms and optionally one ormore heteroatoms, such as nitrogen, oxygen or sulfur atoms for example,be substituted with a substituent, it is possible for said substituentto be bound at any suitable position of said ring, be it bound to asuitable carbon atom and/or to a suitable heteroatom.

The term “comprising” when used in the specification includes“consisting of”.

If within the present text any item is referred to as “as mentionedherein”, it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:The term “halogen atom” means a fluorine, chlorine, bromine or iodineatom, particularly a fluorine, chlorine or bromine atom.

The term “C₁-C₈-alkyl” means a linear or branched, saturated, monovalenthydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, heptyl or octyl group, or an isomer thereof.Particularly, said group has 1, 2, 3, 4, 5 or 6 carbon atoms(“C₁-C₆-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl,1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group.Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”),e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, ortert-butyl group, more particularly 1, 2 or 3 carbon atoms(“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.

The term “C₁-C₆-hydroxyalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₁-C₆-alkyl” is definedsupra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxygroup, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl,1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl,1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methylpropyl,2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.Particularly, said group has 1, 2 or 3 carbon atoms(“C₁-C₃-hydroxyalkyl”), e.g. a hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl,2,3-dihydroxypropyl or 1,3-dihydroxypropan-2-yl group.

The term “C₁-C₆-cyanoalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₁-C₆-alkyl” is definedsupra, and in which 1 or 2 hydrogen atoms are replaced with a cyanogroup, e.g. a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1,2-dicyanoethyl,3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl, 1-hydroxypropan-2-yl,2-cyanopropan-2-yl, 2,3-dicyanopropyl, 1,3-dicyanopropan-2-yl,3-cyano-2-methylpropyl, 2-cyano-2-methyl-propyl, 1-cyano-2-methyl-propylgroup. Particularly, said group has 1, 2 or 3 carbon atoms(“C₁-C₃-cyanoalkyl”), e.g. a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl,1,2-dicyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl,1-cyanopropan-2-yl, 2-cyanopropan-2-yl, 2,3-dicyanopropyl or1,3-dicyanopropan-2-yl group, more particularly, said group has 1, 2 or3 carbon atoms (“C₁-C₃-cyanoalkyl”), e.g. a cyanomethyl, 1-cyanoethyl,2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl,1-cyanopropan-2-yl or 2-cyanopropan-2-yl group.

The term “C₁-C₆-alkylsulfanyl” means a linear or branched, saturated,monovalent group of formula (C₁-C₆-alkyl)-S—, in which the term“C₁-C₆-alkyl” is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl,propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl,isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl,hexylsulfanyl group.

The term “C₂-C₈-haloalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₂-C₈-alkyl” is asdefined supra, and in which one or more of the hydrogen atoms arereplaced, identically or differently, with a halogen atom. Particularly,said halogen atom is a fluorine atom. Said C₂-C₈-haloalkyl group is, forexample, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.Particularly, said group has 2, 3, 4 5 or 6 carbon atoms(“C₂-C₆-haloalkyl”).

The term “C₁-C₆-haloalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₁-C₆-alkyl” is asdefined supra, and in which one or more of the hydrogen atoms arereplaced, identically or differently, with a halogen atom. Particularly,said halogen atom is a fluorine atom. Said C₁-C₆-haloalkyl group is, forexample, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl. Particularly, saidgroup has 1, 2, 3 or 4 carbon atoms (“C₁-C₄-haloalkyl”), moreparticularly 1, 2 or 3 carbon atoms (“C₁-C₃-haloalkyl”), e.g.fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.

For any alkyl group being substituted the position of the substitutentmay be at any position of the alkyl group independently whether thealkyl group is defined as “an alkyl group which is substituted by[substituent X]” or “a [substituent X]—C₁-C₆-alkyl” group.

The term “C₁-C₆-alkoxy” means a linear or branched, saturated,monovalent group of formula (C₁-C₆-alkyl)-O—, in which the term“C₁-C₆-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy,isopentyloxy or n-hexyloxy group, or an isomer thereof. Particularly,said group has 1, 2 or 3 carbon atoms (“C₁-C₃-alkoxy”), e.g. a methoxy,ethoxy, n-propoxy or isopropoxy group.

The term “C₁-C₆-haloalkoxy” means a linear or branched, saturated,monovalent C₁-C₆-alkoxy group, as defined supra, in which one or more ofthe hydrogen atoms is replaced, identically or differently, with ahalogen atom. Particularly, said halogen atom is a fluorine atom. SaidC₁-C₆-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.Particularly, said group has 1, 2 or 3 carbon atoms(“C₁-C₃-haloalkoxy”), e.g. a fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy group.

The term “C₂-C₆-alkenyl” means a linear or branched, monovalenthydrocarbon group, which contains one double bond, and which has 2, 3,4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms(“C₂-C₃-alkenyl”), it being understood that in the case in which saidalkenyl group contains more than one double bond, then it is possiblefor said double bonds to be isolated from, or conjugated with, eachother. Said alkenyl group is, for example, an ethenyl (or “vinyl”),prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl,but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl,hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl,prop-1-en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl,1-methylprop-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl,3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl,3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl,3-methylbut-1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl,1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl,1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl,2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl,3-methylpent-3-enyl, 2-methylpent-3-enyl, 1-methylpent-3-enyl,4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl,1-methylpent-2-enyl, 4-methylpent-1-enyl, 3-methylpent-1-enyl,2-methylpent-1-enyl, 1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, 3-ethylbut-2-enyl,2-ethylbut-2-enyl, 1-ethylbut-2-enyl, 3-ethylbut-1-enyl,2-ethylbut-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl,1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl,2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl,1-isopropylprop-1-enyl, 3,3-dimethylprop-1-enyl, or1-(1,1-dimethylethyl)ethenyl group. Particularly, said group is allyl.

The term “C₂-C₆-alkynyl” means a linear or branched, monovalenthydrocarbon group which contains one triple bond, and which contains 2,3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms(“C₂-C₃-alkynyl”). Said C₂-C₆-alkynyl group is, for example, ethynyl,prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl,but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl,hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methyl-pent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methyl-pent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynylgroup.

The term “bicyclic aryl group means an aromatic ring system selectedfrom naphthyl, indenyl.

The term “partially saturated mono- or bicyclic aryl- or heteroaryl”includes dihydrophenyl, tetrahydrophenyl, 5- to 7-memberedheterocycloalkenyl (as further defined below), indanyl, tetralinyl,tetralonyl, dihydroquinolinyl, tetrahydroquinolinyl,dihydroquinazolinyl, tetrahydroquinazolinyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, dihydrocinnolinyl, tetrahydrocinnolinyl,dihydrophthalazinyl, tetrahydrophthalazinyl, dihydroquinoxalinyl,tetrahydroquinoxalinyl, dihydropteridinyl or tetrahydropteridinyl,dihydroindolyl, dihydrobenzofuranyl, dihydrobenzothienyl,dihydrobenzimidazolyl dihydrobenzoxazolyl, dihydrobenzisoxazolyl,dihydrobenzimidazolyl, dihydrobenzothiazolyl, dihydrobenzotriazolyl,dihydroindazolyl, dihydroisoindolyl, dihydroindolizinyl ordihydropurinyl.

The term “C₃-C₈-cycloalkyl” means a saturated, monovalent, mono- orbicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms(“C₃-C₈-cycloalkyl”). Said C₃-C₈-cycloalkyl group is for example, amonocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclichydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.Particularly, said group contains 3, 4, 5 or 6 carbon atoms(“C₃-C₆-cycloalkyl”), e.g. a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl group. Particularly, said group contains 4, 5, 6, 7 or 8carbon atoms (“C₄-C₈-cycloalkyl”), e.g. a cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl group.

The term “C₄-C₈-cycloalkenyl” means a monovalent, mono- or bicyclichydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and onedouble bond. Particularly, said ring contains 4, 5 or 6 carbon atoms(“C₄-C₆-cycloalkenyl”). Said C₄-C₈-cycloalkenyl group is for example, amonocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclichydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl orbicyclo[2.2.2]oct-2-enyl.

The term “C₃-C₈-cycloalkoxy” means a saturated, monovalent, mono- orbicyclic group of formula (C₃-C₈-cycloalkyl)-O—, which contains 3, 4, 5,6, 7 or 8 carbon atoms, in which the term “C₃-C₈-cycloalkyl” is definedsupra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group. Particularly, saidgroup has 3, 4, 5 or 6 carbon atoms (“C₃-C₆-cycloalkoxy”), e.g. acyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.

The terms “4- to 7-membered heterocycloalkyl” and “4- to 6-memberedheterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains oneor two identical or different ring heteroatoms from the series N, O andS being possible for said heterocycloalkyl group to be attached to therest of the molecule via any one of the carbon atoms or, if present andnot excluded otherwise, a nitrogen atom.

Said heterocycloalkyl group, without being limited thereto, can be a4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example;or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl,thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or1,3-thiazolidinyl, for example; or a 6-membered ring, such astetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl,1,4-diazepanyl or 1,4-oxazepanyl, for example.

The terms “4- to 7-membered nitrogen containing heterocycloalkyl” and“4- to 6-membered nitrogen containing heterocycloalkyl” mean amonocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4,5 or 6 ring atoms in total, containing one ring nitrogen atom andoptionally one further ring heteroatom from the series: N, O, S atom.

Said nitrogen containing heterocycloalkyl group, without being limitedthereto, can be a 4-membered ring, such as azetidinyl for example; or a5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl,1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; ora 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl or 1,2-oxazinanyl, for example, or a 7-membered ring, suchas azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example.

The term “5- to 7-membered heterocycloalkenyl” means a monocyclic,unsaturated, non-aromatic heterocycle with 5, 6 or 7 ring atoms intotal, which contains one or two double bonds and one or two ringheteroatoms independently selected from the series: N, O, S.

Said heterocycloalkenyl group is, for example, 4H pyranyl, 2H pyranyl,2,5 dihydro 1H pyrrolyl, [1,3]dioxolyl, 4H [1,3,4]thiadiazinyl, 2,5dihydrofuranyl, 2,3 dihydrofuranyl, 2,5 dihydrothio-phenyl, 2,3dihydrothiophenyl, 4,5 dihydrooxazolyl or 4H [1,4]thiazinyl.

The term “4-7-membered, optionally unsaturated, heterocyclic group”includes the terms “4- to 7-membered heterocycloalkyl” and “5- to7-membered heterocycloalkenyl”.

The term “aryl” means phenyl and naphthyl.

The term “phenyl groups of which two vicinal substituents may formtogether a 5- or 6-membered, optionally aromatic or non-aromatic ring,and optionally containing a C(═O) group” includes naphthalinyl, indanyland tetralinyl.

The term “heteroaryl” means a monovalent, monocyclic or bicyclicaromatic ring having 5, 6, 8, 9 or 10 ring atoms (a “5- to 10-memberedheteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, whichcontains at least one ring heteroatom and optionally one, two or threefurther ring heteroatoms from the series: N, O and/or S, and which isbound via a ring carbon atom or optionally via a ring nitrogen atom (ifallowed by valency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, forexample, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as,for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl; or a 9-membered heteroaryl group, such as, for example,benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl,benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl,isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group,such as, for example, quinolinyl, quinazolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

In general, and unless otherwise mentioned, the heteroaryl orheteroarylene groups include all possible isomeric forms thereof, e.g.:tautomers and positional isomers with respect to the point of linkage tothe rest of the molecule. Thus, for some illustrative non-restrictingexamples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl andpyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

The term “C₁-C₆”, as used in the present text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”,“C₁-C₆-hydroxyalkyl”, “C₁-C₆-alkoxy” or “C₁-C₆-haloalkoxy” means analkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2,3, 4, 5 or 6 carbon atoms.

Further, as used herein, the term “C₃-C₈”, as used in the present text,e.g. in the context of the definition of “C₃-C₈-cycloalkyl”, means acycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms.

When a range of values is given, said range encompasses each value andsub-range within said range.

For example:

“C₁-C₈” encompasses C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₁-C₈, C₁-C₇, C₁-C₆,C₁-C₅, C₁- C₄, C₁-C₃, C₁-C₂, C₂-C₈, C₂-C₇, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃,C₃-C₈, C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₈, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₈,C₅-C₇, C₅-C₆, C₆-C₈, C₆-C₇ and C₇-C₈;

“C₁-C₆” encompasses C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃,C₁-C₂, C₂- C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅,and C₅-C₆;

“C₁-C₄” encompasses C₁, C₂, C₃, C₄, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₄, C₂-C₃and C₃-C₄;

“C₁-C₃” encompasses C₁, C₂, C₃, C₁-C₃, C₁-C₂ and C₂-C₃;

“C₂-C₆” encompasses C₂, C₃, C₄, C₅, C₆, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃,C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆;

“C₃-C₈” encompasses C₃, C₄, C₅, C₆, C₇, C₈, C₃-C₈, C₃-C₇, C₃-C₆, C₃-C₅,C₃-C₄, C₄- C₈, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₈, C₅-C₇, C₅-C₆, C₆-C₈, C₆-C₇and C₇-C₈;

“C₃-C₆” encompasses C₃, C₄, C₅, C₆, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅,and C₅-C₆;

“C₄-C₈” encompasses C₄, C₅, C₆, C₇, C₈, C₄-C₈, C₄-C₇, C₄-C₆, C₄-C₅,C₅-C₈, C₅-C₇, C₅-C₆, C₆-C₈, C₆-C₇ and C₇-C₈;

“C₄-C₇” encompasses C₄, C₅, C₆, C₇, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₇, C₅-C₆and C₆-C₇;

“C₄-C₆” encompasses C₄, C₅, C₆, C₄-C₆, C₄-C₅ and C₅-C₆;

“C₅-C₁₀” encompasses C₅, C₆, C₇, C₈, C₉, C₁₀, C₅-C₁₀, C₅-C₉, C₅-C₈,C₅-C₇, C₅-C₆, C₆- C₁₀, C₆-C₉, C₆-C₈, C₆-C₇, C₇-C₁₀, C₇-C₉, C₇-C₈,C₈-C₁₀, C₈-C₉ and C₉-C₁₀;

“C₆-C₁₀” encompasses C₆, C₇, C₈, C₁₀, C₆-C₁₀, C₆-C₉, C₆-C₈, C₆-C₇,C₇-C₁₀, C₇-C₉, C₇- C₈, C₈-C₁₀, C₈-C₉ and C₉-C₁₀.

As used herein, the term “as defined supra” means as defined anywhere inthe specification and claims.

As used herein, the term “leaving group” means an atom or a group ofatoms that is displaced in a chemical reaction as stable species takingwith it the bonding electrons. In particular, such a leaving group isselected from the group comprising: halide, in particular fluoride,chloride, bromide or iodide, (methylsulfonyl)oxy,[(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)-sulfonyl]oxy,(phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy,[(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy,[(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy,[(2,4,6-triisopropylphenyl)sulfonyl]oxy,[(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butyl-phenyl)sulfonyl]oxyand [(4-methoxyphenyl)sulfonyl]oxy.

The term “substituent” refers to a group “substituted” on, e.g., analkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any atom of that group,replacing one or more hydrogen atoms therein. In one aspect, thesubstituent(s) on a group are independently any one single, or anycombination of two or more of the permissible atoms or groups of atomsdelineated for that substituent. In another aspect, a substituent mayitself be substituted with any one of the above substituents. Further,as used herein, the phrase “optionally substituted” means unsubstituted(e.g., substituted with an H) or substituted.

It will be understood that the description of compounds herein islimited by principles of chemical bonding known to those skilled in theart. Accordingly, where a group may be substituted by one or more of anumber of substituents, such substitutions are selected so as to complywith principles of chemical bonding with regard to valencies, etc., andto give compounds which are not inherently unstable. For example, anycarbon atom will be bonded to two, three, or four other atoms,consistent with the four valence electrons of carbon.

By “subject” is meant a mammal, including, but not limited to, a humanor non-human mammal, such as a bovine, equine, canine, ovine, rodent, orfeline.

It is possible for the compounds of general formula (I) to exist asisotopic variants. The invention therefore includes one or more isotopicvariant(s) of the compounds of general formula (I), particularlydeuterium-containing compounds of general formula (I).

The term “Isotopic variant” of a compound or a reagent is defined as acompound exhibiting an unnatural proportion of one or more of theisotopes that constitute such a compound.

The term “Isotopic variant of the compound of general formula (I)” isdefined as a compound of general formula (I) exhibiting an unnaturalproportion of one or more of the isotopes that constitute such acompound.

The expression “unnatural proportion” in relation to an isotope means aproportion of such isotope which is higher than its natural abundance.The natural abundances of isotopes to be applied in this context aredescribed in “Isotopic Compositions of the Elements 1997”, Pure Appl.Chem., 70(1), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br,¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I, respectively.

With respect to the treatment and/or prophylaxis of the disordersspecified herein the isotopic variant(s) of the compounds of generalformula (I) preferably contain deuterium (“deuterium-containingcompounds of general formula (I)”). Isotopic variants of the compoundsof general formula (I) in which one or more radioactive isotopes, suchas ³H or ¹⁴C, are incorporated are useful e.g. in drug and/or substratetissue distribution studies. These isotopes are particularly preferredfor the ease of their incorporation and detectability. Positron emittingisotopes such as ¹⁸F or ¹¹C may be incorporated into a compound ofgeneral formula (I). These isotopic variants of the compounds of generalformula (I) are useful for in vivo imaging applications.Deuterium-containing and ¹³C-containing compounds of general formula (I)can be used in mass spectrometry analyses in the context of preclinicalor clinical studies.

Isotopic variants of the compounds of general formula (I) can generallybe prepared by methods known to a person skilled in the art, such asthose described in the schemes and/or examples herein, by substituting areagent for an isotopic variant of said reagent, preferably for adeuterium-containing reagent. Depending on the desired sites ofdeuteration, in some cases deuterium from D₂O can be incorporated eitherdirectly into the compounds or into reagents that are useful forsynthesizing such compounds. Deuterium gas is also a useful reagent forincorporating deuterium into molecules. Catalytic deuteration ofolefinic bonds and acetylenic bonds is a rapid route for incorporationof deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence ofdeuterium gas can be used to directly exchange deuterium for hydrogen infunctional groups containing hydrocarbons. A variety of deuteratedreagents and synthetic building blocks are commercially available fromcompanies such as for example C/D/N Isotopes, Quebec, Canada; CambridgeIsotope Laboratories Inc., Andover, Mass., USA; and CombiPhos Catalysts,Inc., Princeton, N.J., USA.

The term “deuterium-containing compound of general formula (I)” isdefined as a compound of general formula (I), in which one or morehydrogen atom(s) is/are replaced by one or more deuterium atom(s) and inwhich the abundance of deuterium at each deuterated position of thecompound of general formula (I) is higher than the natural abundance ofdeuterium, which is about 0.015%. Particularly, in adeuterium-containing compound of general formula (I) the abundance ofdeuterium at each deuterated position of the compound of general formula(I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferablyhigher than 90%, 95%, 96% or 97%, even more preferably higher than 98%or 99% at said position(s). It is understood that the abundance ofdeuterium at each deuterated position is independent of the abundance ofdeuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into acompound of general formula (I) may alter the physicochemical properties(such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc.,2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc.,2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984,19(3), 271]) and/or the metabolic profile of the molecule and may resultin changes in the ratio of parent compound to metabolites or in theamounts of metabolites formed. Such changes may result in certaintherapeutic advantages and hence may be preferred in some circumstances.Reduced rates of metabolism and metabolic switching, where the ratio ofmetabolites is changed, have been reported (A. E. Mutlib et al.,Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in theexposure to parent drug and metabolites can have important consequenceswith respect to the pharmacodynamics, tolerability and efficacy of adeuterium-containing compound of general formula (I). In some casesdeuterium substitution reduces or eliminates the formation of anundesired or toxic metabolite and enhances the formation of a desiredmetabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol.,2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl.Pharmacol., 2000, 169, 102). In other cases the major effect ofdeuteration is to reduce the rate of systemic clearance. As a result,the biological half-life of the compound is increased. The potentialclinical benefits would include the ability to maintain similar systemicexposure with decreased peak levels and increased trough levels. Thiscould result in lower side effects and enhanced efficacy, depending onthe particular compound's pharmacokinetic/pharmacodynamic relationship.ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) andOdanacatib (K. Kassahun et al., WO2012/112363) are examples for thisdeuterium effect. Still other cases have been reported in which reducedrates of metabolism result in an increase in exposure of the drugwithout changing the rate of systemic clearance (e.g. Rofecoxib: F.Schneider et al., Arzneim. Forsch./Drug. Res., 2006, 56, 295;Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs showing this effect may have reduced dosingrequirements (e.g. lower number of doses or lower dosage to achieve thedesired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites ofattack for metabolism. To optimize the above-described effects onphysicochemical properties and metabolic profile, deuterium-containingcompounds of general formula (I) having a certain pattern of one or moredeuterium-hydrogen exchange(s) can be selected. Particularly, thedeuterium atom(s) of deuterium-containing compound(s) of general formula(I) is/are attached to a carbon atom and/or is/are located at thosepositions of the compound of general formula (I), which are sites ofattack for metabolizing enzymes such as e.g. cytochrome P₄₅₀.

In another embodiment the present invention concerns adeuterium-containing compound of general formula (I) having 1, 2, 3 or 4deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention optionally contain one or moreasymmetric centres, depending upon the location and nature of thevarious substituents desired. It is possible that one or more asymmetriccarbon atoms are present in the (R) or (S) configuration, which canresult in racemic mixtures in the case of a single asymmetric centre,and in diastereomeric mixtures in the case of multiple asymmetriccentres. In certain instances, it is possible that asymmetry also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Preferred isomers are those which produce the more desirable biologicalactivity. These separated, pure or partially purified isomers or racemicmixtures of the compounds of this invention are also included within thescope of the present invention. The purification and the separation ofsuch materials can be accomplished by standard techniques known in theart.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., HPLC columns using a chiral phase), with orwithout conventional derivatisation, optimally chosen to maximise theseparation of the enantiomers. Suitable HPLC columns using a chiralphase are commercially available, such as those manufactured by Daicel,e.g., Chiracel OD and Chiracel OJ, for example, among many others, whichare all routinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thepresent invention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to distinguish different types of isomers from each otherreference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30,1976).

Isolation of a single stereoisomer, e.g. a single enantiomer or a singlediastereomer, of a compound of the present invention is achieved by anysuitable state of the art method, such as chromatography, especiallychiral chromatography, for example.

Further, it is possible for the compounds of the present invention toexist as tautomers. For example, any compound of the present inventionwhich contains an imidazopyridine moiety as a heteroaryl group forexample can exist as a 1H tautomer, or a 3H tautomer, or even a mixturein any amount of the two tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also provides useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, and/orco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example, asstructural element of the crystal lattice of the compounds. It ispossible for the amount of polar solvents, in particular water, to existin a stoichiometric or non-stoichiometric ratio. In the case ofstoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-,di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, arepossible. The present invention includes all such hydrates or solvates.

Further, it is possible for the compounds of the present invention toexist in free form, e.g. as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “pharmaceutically acceptable salt” refers to an inorganic ororganic acid addition salt of a compound of the present invention. Forexample, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, or “mineral acid”, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric,phosphoric, or nitric acid, for example, or with an organic acid, suchas formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic,itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic,benzenesulfonic, para-toluenesulfonic, methanesulfonic,2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic,adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic,glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium, magnesium or strontium salt, or analuminium or a zinc salt, or an ammonium salt derived from ammonia orfrom an organic primary, secondary or tertiary amine having 1 to 20carbon atoms, such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine,1,2-ethylenediamine,N-methylpiperidine,N-methyl-glucamine,N,N-dimethyl-glucamine,N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol,2-amino-1,3-propanediol, 3-amino-1,2-propanediol,4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ionhaving 1 to 20 carbon atoms, such as tetramethylammonium,tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium,N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

Those skilled in the art will further recognise that it is possible foracid addition salts of the claimed compounds to be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods. Alternatively, alkali and alkaline earthmetal salts of acidic compounds of the present invention are prepared byreacting the compounds of the present invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

One aspect of the invention are tautomers, an N-oxides, or a saltthereof, and a salt of a tautomer or an N-oxide.

The present invention includes diastereomers, racemates, tautomers,N-oxides, hydrates, solvates, and salts of the compounds of the presentinvention, and mixtures of same.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae relating to salts, such as “hydrochloride”, “trifluoroacetate”,“sodium salt”, or “x HCl”, “x CF₃COOH”, “x Na⁺”, for example, mean asalt form, the stoichiometry of which salt form not being specified.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

Moreover, the present invention also includes prodrugs of the compoundsaccording to the invention. The term “prodrugs” here designatescompounds which themselves can be biologically active or inactive, butare converted (for example metabolically or hydrolytically) intocompounds according to the invention during their residence time in thebody.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra,

in which

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from hydroxy, phenyl and —N(R⁷)(R⁸),            -   and wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy                and hydroxy,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group,        -   wherein said 4-7-membered heterocycloalkyl group and said 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom, and which is            optionally substituted one or two times, each substituent            independently selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl,                C₁-C₃-alkoxy and hydroxy,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), hydroxy, cyano, C₁-C₆-hydroxyalkyl,            C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₆-alkyl)-, —SH, —S—(C₁-C₆-alkyl),            —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂,            —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or        -   wherein two vicinal substituents may form together a 5- or            6-membered, optionally heterocyclic, aromatic or            non-aromatic ring, having optionally 1-3 heteroatoms            independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,            and optionally containing a C(═O) group, and wherein the so            formed ring is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸) and    -   a bicyclic aryl group,    -   a partially saturated mono- or bicyclic aryl- or heteroaryl        group,    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl), C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a C₃-C₈-cycloalkyl            group or a NR⁷R⁸ group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group,    -   a C₂-C₆-alkenyl group,    -   a C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group,    -   a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group and which is            optionally substituted with a C₁-C₃-alkyl group, and    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁴ represents a group selected from,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,                aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,                —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),                S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂,                and —N(R⁷)(R⁸)    -   a C₂-C₆-alkenyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₂-C₆-haloalkyl group,    -   a C₂-C₆-hydroxyalkyl group,    -   a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₁-C₆-alkyl)-O—(C₁-C₆-alkyl) group,    -   a C₂-C₆-alkenyl group,    -   a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group, and    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group,    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group, and    -   a phenyl group        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        C₃-C₆-cycloalkyl group, and a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,    -   which is optionally substituted with a group selected from    -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra,

in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4-7-membered, optionally unsaturated, heterocyclic group,    -   a phenyl group, and    -   a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl,                C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4-7-membered, optionally unsaturated,            heterocyclic group is connected to the rest of the molecule            via a carbon atom,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            hydroxy, aryl, —O-aryl, cyano, —C(O)OH, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and            SF₅,        -   or wherein two vicinal substituents of said phenyl groups            may form together a 5- or 6-membered, optionally            heterocyclic, aromatic or non-aromatic ring, having            optionally 1-3 heteroatoms independently selected from —N═,            —NH—, —N(R⁷)—, —O—, —S—, and optionally containing a C(═O)            group, and wherein the so formed ring is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸) and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,                aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,                —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),                —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group,    -   a phenyl group, and    -   a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl,                C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4-7-membered, optionally unsaturated,            heterocyclic group is connected to the rest of the molecule            via a carbon atom,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            hydroxy, aryl, —O-aryl, cyano, —C(O)OH, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂,            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and            SF₅,        -   or wherein two vicinal substituents of said phenyl groups            may form together a 5- or 6-membered, optionally            heterocyclic, aromatic or non-aromatic ring, having            optionally 1-3 heteroatoms independently selected from —N═,            —NH—, —N(R⁷)—, —O—, —S—, and optionally containing a C(═O)            group, and wherein the so formed ring is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,                aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,                —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),                —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group or a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said- to 7-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl- or heterocycloalkenyl group,    -   a 5- to 7-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said 5- to 7-membered heterocycloalkenyl group            is connected to the rest of the molecule via a carbon atom            of the said heterocycloalkyl- or heterocycloalkenyl group,    -   a phenyl group,        -   wherein said phenyl group is optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,        -   —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group, a tetralinyl group        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a C₃-C₈-cycloalkyl            group or a NR⁷R⁸ group,    -   a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,    -   a phenyl group,        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₈-cycloalkyl group, a        C₂-C₆-haloalkyl group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group, which is optionally substituted with        a hydroxy group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group, and C₃-C₆-cycloalkyl group    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra,

in which

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said- to 7-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl- or heterocycloalkenyl group,    -   a 5- to 7-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said 5- to 7-membered heterocycloalkenyl group            is connected to the rest of the molecule via a carbon atom            of the said heterocycloalkyl- or heterocycloalkenyl group,    -   a phenyl group,        -   wherein said phenyl group is optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group, a tetralinyl group        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a C₃-C₈-cycloalkyl            group or a NR⁷R⁸ group,    -   a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,    -   a phenyl group,        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₈-cycloalkyl group, a        C₂-C₆-haloalkyl group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group, which is optionally substituted with        a hydroxy group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group, and C₃-C₆-cycloalkyl group    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a        (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a        —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 7-membered        heterocycloalkyl group,    -   a 5- to 7-membered heterocycloalkenyl group, a phenyl group, an        indanyl group, a tetralinyl group and a monocyclic—or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from C₁-C₃-alkyl, 5- to            6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl),            —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl),            —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl,                C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   wherein said C₁-C₆-alkyl group is optionally substituted with a        group selected from    -   C₃-C₈-cycloalkyl and phenyl,        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, or a salt thereof, and a salt of a        tautomer or an N-oxide.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group,    -   a 5- to 7-membered heterocycloalkenyl group, a phenyl group, an        indanyl group, a tetralinyl group and a monocyclic—or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, or a salt thereof, and a salt of a        tautomer or an N-oxide.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group or a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a (C₂-C₃-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a 5- to 6-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 5- to 6-membered heterocycloalkenyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a tetralinyl group and        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₆-cycloalkyl group, a        C₂-C₆-haloalkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₄-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group, a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and C₃-C₆-cycloalkyl group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or    a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a 5- to 6-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 5- to 6-membered heterocycloalkenyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a tetralinyl group and        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₆-cycloalkyl group, a        C₂-C₆-haloalkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₄-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group, a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and C₃-C₆-cycloalkyl group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or    a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₂-C₈-haloalkyl group, a C₄-C₈-cycloalkyl        group,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a        (C₂-C₃-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a        —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered        heterocycloalkyl group, a 5- to 6-membered heterocycloalkenyl        group, a phenyl group, an indanyl group, a tetralinyl group and        a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and            said 5- to 6-membered heterocycloalkenyl group are            optionally substituted one or two times, each substituent            independently selected from a group selected from            C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and            said 5- to 6-membered heterocycloalkenyl group are connected            to the rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group, and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl- or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₄-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group and a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or    a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 6-membered heterocycloalkyl    group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with certain embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,    -   a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered        heterocycloalkenyl group, a phenyl group, an indanyl group, a        tetralinyl group and a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and            said 5- to 6-membered heterocycloalkenyl group are            optionally substituted one or two times, each substituent            independently selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and            said 5- to 6-membered heterocycloalkenyl group are connected            to the rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl- or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₄-alkyl group and a benzyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group and a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,    -   wherein said 4- to 6-membered nitrogen containing        heterocycloalkyl group is optionally substituted with a group        selected from    -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),-   R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or    a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, with a            phenyl group, wherein said phenyl substituent is optionally            substituted, one, two or three times, each substituent            independently selected from a halogen atom,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a hydroxy group or        a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom of the said heterocycloalkyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three or four            times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,    -   an indanyl group and    -   a monocyclic- or bicyclic heteroaryl group,        -   which are optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group-   R⁴ represents a group selected from    -   a C₂-C₆-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from            C₃-C₆-cycloalkyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₁-C₆-alkoxy group,    -   C₁-C₆-alkylsulfanyl group,    -   —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group or a cyclopropyl group,-   R¹¹ represents a hydrogen atom,-   or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, with a            phenyl group,        -   wherein said phenyl substituent is optionally substituted,            one, two or three times, each substituent independently            selected from a halogen atom,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom of the said heterocycloalkyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three or four            times, each substituent independently selected from a            halogen atom or a group selected from C₁-C₄-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,    -   an indanyl group and    -   a monocyclic- or bicyclic heteroaryl group,        -   which are optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group-   R⁴ represents a group selected from    -   a C₂-C₆-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from            C₃-C₆-cycloalkyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₁-C₆-alkoxy group,    -   C₁-C₆-alkylsulfanyl group,    -   —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group or a cyclopropyl group,-   R¹¹ represents a hydrogen atom,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₄-C₈-cycloalkyl group,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered        heterocycloalkyl group,    -   a phenyl group, an indanyl group and a monocyclic- or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, with a phenyl group,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, each substituent            independently selected from a C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three or four times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, a        —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group and    -   a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,-   R¹¹ represents a hydrogen atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,    -   a 4- to 6-membered heterocycloalkyl group,    -   a phenyl group, an indanyl group and a monocyclic- or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, with a phenyl group,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, each substituent            independently selected from a C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three or four times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a        -   C₃-C₆-cycloalkyl group,-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, a        —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group and    -   a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,-   R¹¹ represents a hydrogen atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with other embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group,    -   a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₇-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a phenyl group,    -   a C₂-C₅-hydroxyalkyl group,    -   a —(C₃-C₅-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₅-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl,            —S(═O)(═NH)(C₁-C₃-alkyl) and    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group or a NR⁷R⁸ group,-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,    -   a C₁-C₅-alkyl group,        -   which is optionally substituted with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₃-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₃-hydroxyalkyl group,    -   (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)- group,    -   a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group,    -   a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group or a cyclopropyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with other embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group, and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl,            —S(═O)(═NH)(C₁-C₃-alkyl) and    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group or a NR⁷R⁸ group,-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₁-C₃-hydroxyalkyl group,    -   a C₁-C₅-alkyl group,        -   which is optionally substituted with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₃-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₃-hydroxyalkyl group,    -   (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)- group,    -   a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group,    -   a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group or a cyclopropyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with other embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₇-cycloalkyl        group,    -   a C₂-C₅-hydroxyalkyl group, a —(C₃-C₅-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₅-alkyl)-C(═O)N(R⁷)(R⁸) group, a 5- to 6-membered        heterocycloalkyl group,    -   a phenyl group, an indanyl group, and a monocyclic heteroaryl        group,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,-   R⁴ represents a group selected from    -   a C₁-C₅-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)-        group, a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group, a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with other embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group,    -   a phenyl group, an indanyl group, and a monocyclic heteroaryl        group,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,-   R⁴ represents a group selected from    -   a C₁-C₅-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group, wherein said C₁-C₄-alkyl group is        optionally substituted with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)-        group, a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group, a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,-   and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group,    -   a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a phenyl group,    -   a C₂-C₄-hydroxyalkyl group,    -   a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group,    -   a CH₃CH₂CH—C(═O)NH₂ group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl,            —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and            —(C₁-C₃-alkyl)-N(R⁷)(R⁸),    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group or a N(R⁷)(R⁸) group,-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₃-hydroxyalkyl group,    -   a C₁-C₄-alkyl group,        -   which is optionally substituted with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₃-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₃-hydroxyalkyl group,    -   a CH₃O—(C₁-C₂-alkyl)- group,    -   a C₁-C₃-alkoxy group,    -   a methylsulfanyl group,    -   a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a methyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group or a cyclopropyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl,            —S(═O)(═NH)(C₁-C₃-alkyl) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a halogen atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group or a N(R⁷)(R⁸) group,-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₃-hydroxyalkyl group,    -   a C₁-C₄-alkyl group,        -   which is optionally substituted with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₃-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₃-hydroxyalkyl group,    -   a CH₃O—(C₁-C₂-alkyl)- group,    -   a C₁-C₃-alkoxy group,    -   a methylsulfanyl group,    -   a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group-   R⁶ represents a hydrogen atom or a methyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group or a cyclopropyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl        group,    -   a C₃-C₄-hydroxyalkyl group, a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group, a        CH₃CH₂CH—C(═O)NH₂ group, a 5- to 6-membered heterocycloalkyl        group, a phenyl group, an indanyl group, and a monocyclic        heteroaryl group,        -   wherein said 5- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, with a C₁-C₃-alkyl            group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   wherein said monocyclic heteroaryl group is optionally            substituted one or two times, each substituent independently            selected from a group selected from C₁-C₃-alkyl and            C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a methoxy-(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a        —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a methyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    or a tautomer, an N-oxide, or a salt thereof, and a salt of a    tautomer or an N-oxide.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group, a phenyl group, an        indanyl group, and a monocyclic heteroaryl group,        -   wherein said 5- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, with a C₁-C₃-alkyl            group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   wherein said monocyclic heteroaryl group is optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a methoxy-(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a        —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a methyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    and a tautomer, an N-oxide, or a salt thereof, and a salt of a    tautomer or an N-oxide.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl        group,    -   a C₃-C₄-hydroxyalkyl group, a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group, a        CH₃CH₂CH—C(═O)NH₂ group, a 5- to 6-membered heterocycloalkyl        group, a phenyl group, an indanyl group, and a monocyclic        heteroaryl group,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuranyl, tetrahydro-2H-pyranyl and            piperidinyl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazolyl, pyrazolyl, pyridinyl and pyrimidinyl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a methoxy-(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a        —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a methyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl,        4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclopentylmethyl, cyclohexylmethyl, 1-cyclohexylethyl,        1-hydroxypropan-2-yl,    -   2-hydroxypropyl, 1-hydroxybutan-2-yl, 1-cyanobutan-2-yl,        1-phenylbutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        1-amino-1-oxobutan-2-yl, indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl,        -   and which is optionally substituted one or two times with a            methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each        -   substituent independently selected from a fluorine atom or a            chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,-   R² represents a hydrogen atom or a fluorine or chlorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,        cyclohexyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,        prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, N,N-dimethylaminoethyl,        and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        1-chloroethyl, 1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl,        methoxy, isopropoxy, methylsulfanyl, aminomethyl,        (methylamino)methyl, (dimethylamino)methyl, 1-aminoethyl,        2-aminoethyl, methylamino and ethyl(methyl)amino, —C(═O)OH,        —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHcyclopropyl,        —C(═O)N(CH₃)₂, and —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclohexylmethyl, 1-indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl, and which is optionally substituted one or two        times with a methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl, and which is optionally            substituted one or two times, each substituent independently            selected from methyl and methoxy,-   R² represents a hydrogen atom or a fluorine or chlorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,        cyclohexyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,        prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, N,N-dimethylaminoethyl,        and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, hydroxy(trifluoromethyl)methyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-chloroethyl,        1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl, methoxy,        isopropoxy, methylsulfanyl, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,        —C(═O)NHCH₃, —C(═O)NHcyclopropyl, —C(═O)N(CH₃)₂, and        —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl,        4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclopentylmethyl, cyclohexylmethyl, 1-cyclohexylethyl,        1-hydroxypropan-2-yl,    -   2-hydroxypropyl, 1-hydroxybutan-2-yl, 1-cyanobutan-2-yl,        1-phenylbutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        1-amino-1-oxobutan-2-yl, indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl,        -   and which is optionally substituted one or two times with a            methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,        cyclohexyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,        prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, N,N-dimethylaminoethyl,        and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃,        —C(═O)NHcyclopropyl, —C(═O)N(CH₃)₂, and —S(═O)(═NH)CH₃,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, hydroxy(trifluoromethyl)methyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-chloroethyl,        1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl, methoxy,        isopropoxy, methylsulfanyl, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl, and which is optionally substituted one or two        times with a methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,        cyclohexyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,        prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, N,N-dimethylaminoethyl,        and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, hydroxy(trifluoromethyl)methyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-chloroethyl,        1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl, methoxy,        isopropoxy, methylsulfanyl, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,        —C(═O)NHCH₃, —C(═O)NHcyclopropyl, —C(═O)N(CH₃)₂, and        —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclopentylmethyl, cyclohexylmethyl,        1-cyclohexylethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl,        1-hydroxybutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        CH₃CH₂CH—C(═O)NH₂, 5- to 6-membered heterocycloalkyl, phenyl,        indan-2-yl and monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl            and piperidin-4-yl, which 5- to 6-membered heterocycloalkyl            group is optionally substituted one or two times, with a            methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃, amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,            pyridin-4-yl, pyrimidin-2-yl and pyrimidin-4-yl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   methyl and methoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        trifluoromethyl, allyl, 2-methyl-prop1-enyl and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, cyclopropylmethyl,        benzyl, cyclopropyl, cyclopentyl and 2-hydroxyethyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        1-methoxyethyl, methoxy, isopropoxy, methylsulfanyl,        aminomethyl, (methylamino)methyl, (dimethylamino)methyl,        1-aminoethyl, 2-aminoethyl, methylamino and ethyl(methyl)amino,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from    -   cyclopentyl, cyclohexyl, cycloheptyl,    -   CH₃CH₂CH—C(═O)NH₂,    -   5- to 6-membered heterocycloalkyl, phenyl, indan-2-yl and        monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl            and piperidin-4-yl, which 5- to 6-membered heterocycloalkyl            group is optionally substituted one or two times, with a            methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃, amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,            pyridin-4-yl, pyrimidin-2-yl and pyrimidin-4-yl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   methyl and methoxy,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        trifluoromethyl, allyl, 2-methyl-prop1-enyl and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, cyclopropylmethyl,        benzyl, cyclopropyl, cyclopentyl and 2-hydroxyethyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        1-methoxyethyl, methoxy, isopropoxy, methylsulfanyl,        aminomethyl, (methylamino)methyl, (dimethylamino)methyl,        1-aminoethyl, 2-aminoethyl, methylamino and ethyl(methyl)amino,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, selected from

-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenyl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide,-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]-N-[3-(trifluoromethyl)phenyl]benzamide,-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-[(1S)-1-phenylethoxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide,-   5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(trifluoromethyl)phenyl]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(trifluoromethyl)phenyl]benzamide,-   N-(3-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-cyano-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2,2-dimethylpropyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-cycloheptyl-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-hydroxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(cyclohexylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(1-cyclohexylethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,    mixture of stereoisomers,-   N-(2,4-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[2-(methylamino)phenyl]-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(propan-2-yl)phenyl]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-(2-propylphenyl)benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(propan-2-yl)phenyl]benzamide,-   N-(2,3-dihydro-1H-inden-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(cyclopentylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(4-amino-2,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-amino-4,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-[4-(aminomethyl)-3-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pentan-2-yloxy)benzamide,-   4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihyro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(1S)-1-phenylethoxy]benzamide,-   N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-fluoro-2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   N-[(2R)-1-amino-1-oxobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(heptan-4-yl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   2-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,    mixture of stereoisomers,-   N-(2-amino-6-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,    mixture of stereoisomers,-   N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,    mixture of stereoisomers,-   2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,    mixture of stereoisomers,-   5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,    mixture of stereoisomers,-   N-(2-amino-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pent-4-en-2-yloxy)benzamide,    mixture of stereoisomers,-   N-(2,6-dimethylphenyl)-5-fluoro-4-{3-[(1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2R)-pentan-2-yloxy]benzamide,    mixture of stereoisomers,-   N-(4-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[pent-4-en-2-yloxy]benzamide,    mixture of stereoisomers,-   5-fluoro-4-{4-methyl-3-[(methylamino)methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,    mixture of stereoisomers,-   4-[3-(aminomethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-[4-amino-2-(trifluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   N-[2-(aminomethyl)-6-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,-   4-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluorobenzamide,    mixture of stereoisomers,-   4-(4-cyclopentyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-{3-[ethyl(methyl)amino]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    single stereomer,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-{3-[(dimethylamino)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-(4-methyl-5-oxo-3-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[3-(2-aminoethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylamino)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-tert-butyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-chloro-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[4-(cyclopropylmethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-(3-methyl-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-[3-ethyl-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3,4-diethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-cyclopropyl-3-methoxy-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-chloro-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopentyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[4-(butan-2-yl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    mixture of stereoisomers,-   4-[3-(butan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    mixture of stereoisomers,-   N-(2,6-difluorophenyl)-4-[4-ethyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-methoxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    mixture of stereoisomers,-   N-(2,6-difluorophenyl)-4-[4-ethyl-5-oxo-3-(propan-2-yloxy)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(4-benzyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(tetrahydrofuran-3-yl)benzamide,    mixture of stereoisomers,-   5-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1H-pyrazol-3-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-2-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-4-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1-methylpiperidin-4-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(tetrahydro-2H-pyran-4-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyrimidin-4-yl)benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1,3-oxazol-2-yl)benzamide,-   5-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   N-cyclopentyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   N-cyclohexyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-hydroxypropyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,    mixture of stereoisomers,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-phenylbenzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyrimidin-2-yl)benzamide,-   N-[(2R)-1-aminopropan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   N-[(2R)-1-aminobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,-   5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(piperidin-4-yl)benzamide,-   2-(1-cyclohexylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   2-[(1-cyclopropylpropan-2-yl)oxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   2-(1-cyclopentylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   2-(1-cyclopropylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(1-phenylethoxy)benzamide,    mixture of stereoisomers,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-[(3-ethylpentan-2-yl)oxy]-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(4-methylpent-3-en-2-yl)oxy]-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(pent-4-en-2-yloxy)benzamide,    mixture of stereoisomers,-   2-(1-cyclobutylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,    mixture of stereoisomers,-   5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,    mixture of stereoisomers, and-   5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,    mixture of stereoisomers,    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I), supra, selected from

-   N-(2-chloro-6-fluorophenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide    (Racemic)-   N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide    (Racemic)-   N-(2-chloro-6-fluorophenyl)-4-[4-cyclopropyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-cyclobutyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-2-{[3,3-difluorobutan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluorobenzamide    (Racemic),-   5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2-chloro-6-fluorophenyl)-3-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(6-chloro-2-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   3-chloro-4-(4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamido)-5-fluorophenyl    2,2-dimethylpropanoate,-   N-(2-chloro-6-fluoro-4-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   2-[(1S)-1-cyclohexylethoxy]-N-(1,4-dimethyl-1H-pyrazol-3-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzamide,-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[1-(4-fluorophenyl)cyclopropyl]benzamide-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(oxan-4-yl)benzamide-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-phenylbutan-2-yl)benzamide-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[3-(methanesulfonyl)phenyl]benzamide,-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-methyl-1H-pyrazol-5-yl)benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(methylsulfanyl)phenyl]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylpyridin-3-yl)-2-[(1S)-1-phenylethoxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylquinolin-5-yl)-2-[(1S)-1-phenylethoxy]benzamide,-   N-[3-(cyclopropylcarbamoyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide,-   N-[2-(difluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(6-methyl-1H-indazol-5-yl)-2-[(1S)-1-phenylethoxy]benzamide,-   N-(1-cyanobutan-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide,-   2-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)benzamide,-   2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(S-methanesulfonimidoyl)phenyl]benzamide    (mixture of stereoisomers),-   N-(2,6-difluorophenyl)-4-[4-ethyl-3-(S-methanesulfonimidoyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    (Mixture of stereoisomers),-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   4-ethyl-1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-dichlorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[1,1-difluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid (Racemic),-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-5-{[3,3-difluorobutan-2-yl]oxy}-2-fluorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid (racemic),-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide,-   N-cyclopropyl-1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-N,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-N,N-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide-   Methyl    1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylate,-   5-fluoro-4-{3-[1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    (Mixture of stereoisomers) and-   4-{4-ethyl-5-oxo-3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    (mixture of stereoisomers)    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I), supra, which are exemplified inthe experimental section.

-   In further embodiments, the present invention provides compounds of    formula (I), supra, any compound selected from-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide,-   4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihyro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-cyclobutyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-4-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-difluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   4-ethyl-1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2,6-dichlorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid,-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-5-{[3,3-difluorobutan-2-yl]oxy}-2-fluorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid (racemic),-   1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic    acid, and-   1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide,    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, any compound selected from

-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    single stereomer-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-5-fluoro-4-(3-methyl-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2,6-dichlorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,-   N-(2-chloro-6-fluoro-4-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    and-   N-(2-chloro-6-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, any compound selected from

-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    and-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In another embodiment, the present invention provides a compound offormula (I), supra, which is

-   5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In another embodiment, the present invention provides a compound offormula (I), supra, which is

-   N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide    and    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In another embodiment, the present invention provides a compound offormula (I), supra, which is

-   N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,    or a tautomer, an N-oxide, a salt, a salt a tautomer or a salt of an    N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, selected from

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   and wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy                and hydroxy,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group, a C₃-C₈-heterocycloalkyl group or a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group,        -   wherein said 4-7-membered heterocycloalkyl group and said 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom, and which is            optionally substituted one or two times, each substituent            independently selected from a group selected from    -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl),        —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl),        —S(═O)₂(C₁-C₆-alkyl) and    -   oxo (═O),        -   wherein said 5- to 6-membered heteroaryl substituent is            optionally substituted, one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), hydroxy, cyano, C₁-C₆-hydroxyalkyl,            C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₆-alkyl)-, —SH, —S—(C₁-C₆-alkyl),            —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂,            —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or        -   wherein two vicinal substituents may form together a 5- or            6-membered, optionally heterocyclic, aromatic or            non-aromatic ring, having optionally 1-3 heteroatoms            independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,            and optionally containing a C(═O) group, and wherein the so            formed ring is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and    -   a bicyclic aryl group,    -   a partially saturated mono- or bicyclic aryl- or heteroaryl        group,    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl), C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸),            or a tautomer, an N-oxide, a salt, a salt a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₂-C₈-haloalkyl group, a C₄—C-cycloalkyl        group,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a        (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a        —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4-7-membered,        optionally unsaturated, heterocyclic group, a phenyl group, and        a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4-7-membered, optionally unsaturated,            heterocyclic group is connected to the rest of the molecule            via a carbon atom,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            hydroxy, aryl, —O-aryl, cyano, —C(O)OH, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and            SF₅,        -   or wherein two vicinal substituents of said phenyl groups            may form together a 5- or 6-membered, optionally            heterocyclic, aromatic or non-aromatic ring, having            optionally 1-3 heteroatoms independently selected from —N═,            —NH—, —N(R⁷)—, —O—, —S—, and optionally containing a C(═O)            group, and wherein the so formed ring is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group or a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-cyanoalkyl- group,    -   a —(C₂-C₆-alkyl)phenyl group,    -   a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said- to 7-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl- or heterocycloalkenyl group,    -   a 5- to 7-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said 5- to 7-membered heterocycloalkenyl group            is connected to the rest of the molecule via a carbon atom            of the said heterocycloalkyl- or heterocycloalkenyl group,    -   a phenyl group, wherein said phenyl groups are optionally        substituted, one, two, three, four or five times, each        substituent independently selected from a halogen atom or a        group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group, a tetralinyl group, wherein said indanyl or        tetralinyl group is optionally substituted one or two times,        each substituent independently selected from a halogen atom or a        group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸), and    -   a monocyclic—or bicyclic heteroaryl group,        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            or a tautomer, an N-oxide, a salt, a salt a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₂-C₃-haloalkyl group, a C₄-C₈-cycloalkyl        group,    -   a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic—or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a        (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a        —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 7-membered        heterocycloalkyl group, a 5- to 7-membered heterocycloalkenyl        group, a phenyl group, an indanyl group, a tetralinyl group and        a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from C₁-C₃-alkyl, 5- to            6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl),            —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl),            —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and            said 5- to 7-membered heterocycloalkenyl group are connected            to the rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in

-   -   which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group, a        hydroxy group or a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-cyanoalkyl- group,    -   a —(C₂-C₆-alkyl)phenyl group,    -   a (C₂-C₃-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a 5- to 6-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 5- to 6-membered heterocycloalkenyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a tetralinyl group and        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸),            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxides thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₂-C₃-haloalkyl group, a C₄-C₈-cycloalkyl        group,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a cyano group or a        phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a        (C₂-C₃-hydroxyalkyl)-O—(C₂-C₆-alky)- group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a        —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered        heterocycloalkyl group, a 5- to 6-membered heterocycloalkenyl        group, a phenyl group, an indanyl group, a tetralinyl group and        a monocyclic—or bicyclic heteroaryl group,    -   wherein said cycloalkyl groups are optionally substituted, one        or two times, each substituent independently selected from a        halogen atom or a group selected from    -   hydroxy, phenyl and —N(R⁷)(R⁸),        -   wherein said phenyl substituent is optionally substituted,            one, two or three times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   and    -   wherein said 4- to 6-membered heterocycloalkyl group and 5- to        6-membered heterocycloalkenyl group are optionally substituted        one or two times, each substituent independently selected from a        group selected from    -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl),        —C(═O)(C₁-C₃-alkyl), —C(═O)(C₃-C₆-cycloalkyl),        —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),        -   wherein said 5- to 6-membered heteroaryl group is optionally            substituted, one, two or three times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   and    -   wherein said 4- to 6-membered heterocycloalkyl group and 5- to        6-membered heterocycloalkenyl group are connected to the rest of        the molecule via a carbon atom of the said heterocycloalkyl- or        heterocyclalkenyl group,    -   and    -   wherein said phenyl groups are optionally substituted, one, two,        three, four or five times, each substituent independently        selected from a halogen atom or a group selected from    -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,        C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),        —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —(C₁-C₃-alkyl)-C(═O)OR⁶,        —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸), —S(═O)₂N(R⁷)(R⁸),        —S(═O)₂(C₁-C₃-alkyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl),        —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl- or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, with a            phenyl group, wherein said phenyl substituent is optionally            substituted, one, two or three times, each substituent            independently selected from a halogen atom,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a hydroxy group or        a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-cyanoalkyl- group,    -   a —(C₂-C₆-alkyl)phenyl group,    -   a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom of the said heterocycloalkyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three or four            times, each substituent independently selected from a            halogen atom or a group selected from C₁-C₄-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,    -   an indanyl group and    -   a monocyclic- or bicyclic heteroaryl group,        -   which are optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₄-C₈-cycloalkyl group,    -   a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl        group,    -   a C₂-C₆-alkyl group which is substituted with a phenyl group,    -   a C₃-C₆-alkyl group which is substituted with a monocyclic or        bicyclic heteroaryl group,    -   a C₂-C₆-hydroxyalkyl group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered        heterocycloalkyl group,    -   a phenyl group, an indanyl group and a monocyclic- or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, with a phenyl group,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, each substituent            independently selected from a C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three or four times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group,    -   a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₇-cycloalkyl        group,    -   a C₂-C₅-alkyl group which is substituted with a cyano group a        hydroxy group or a phenyl group,    -   a —(C₃-C₅-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₅-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl,            —S(═O)(═NH)(C₁-C₃-alkyl) and    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₇-cycloalkyl        group,    -   a C₂-C₅-hydroxyalkyl group, a —(C₃-C₅-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₅-alkyl)-C(═O)N(R⁷)(R⁸) group, a 5- to 6-membered        heterocycloalkyl group,    -   a phenyl group, an indanyl group, and a monocyclic heteroaryl        group,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group,    -   a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl        group,    -   a C₃-C₄-hydroxyalkyl group,    -   a C₃-C₄-phenylalkyl group,    -   a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group,    -   a CH₃CH₂CH—C(═O)NH₂ group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl,            —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and            —(C₁-C₃-alkyl)-N(R⁷)(R⁸),    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group,    -   a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl        group,    -   a C₃-C₄-hydroxyalkyl group, a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group, a        CH₃CH₂CH—C(═O)NH₂ group, a 5- to 6-membered heterocycloalkyl        group, a phenyl group, an indanyl group, and a monocyclic        heteroaryl group,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuranyl, tetrahydro-2H-pyranyl and            piperidinyl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazolyl, pyrazolyl, pyridinyl and pyrimidinyl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl,        4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclopentylmethyl, cyclohexylmethyl, 1-cyclohexylethyl,        1-hydroxypropan-2-yl,    -   2-hydroxypropyl, 1-hydroxybutan-2-yl, 1-cyanobutan-2-yl,        1-phenylbutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        1-amino-1-oxobutan-2-yl, indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl, and which is optionally substituted one or two        times with a methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl,        4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclopentylmethyl, cyclohexylmethyl, 1-cyclohexylethyl,        1-hydroxypropan-2-yl, 2-hydroxypropyl, 1-hydroxybutan-2-yl,        1-phenylbutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        1-amino-1-oxobutan-2-yl, indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl, and which is optionally substituted one or two        times with a methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃, and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclopentylmethyl, cyclohexylmethyl,        1-cyclohexylethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl,        1-hydroxybutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        CH₃CH₂CH—C(═O)NH₂, 5- to 6-membered heterocycloalkyl, phenyl,        indanyl and monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuranyl, tetrahydro-2H-pyranyl and            piperidinyl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃, amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazolyl, pyrazolyl, pyridinyl and pyrimidinyl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   methyl and methoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, 2,2-dimethylpropyl, 4-heptyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclopentylmethyl, cyclohexylmethyl,        1-cyclohexylethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl,        1-hydroxybutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl,        CH₃CH₂CH—C(═O)NH₂, 5- to 6-membered heterocycloalkyl, phenyl,        indan-2-yl and monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl            and piperidin-4-yl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃, amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,            pyridin-4-yl, pyrimidin-2-yl and pyrimidin-4-yl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   methyl and methoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which

-   R¹ represents a phenyl group which is optionally substituted, one,    two, three, four or five times, each substituent independently    selected from a halogen atom or a group selected from C₁-C₆-alkyl,    C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,    —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),    —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),    —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl),    —P(═O)(C₁-C₃-alkyl)₂ and SF₅,    -   or in which two substituents of said phenyl groups, when they        are attached to adjacent ring atoms, are optionally linked to        one another in such a way that they jointly form a group        selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which R¹ represents a phenyl group,which is optionally substituted, one or two times, each substituentindependently selected from a hydroxy group, a fluorine atom, a chlorineatom and a methyl group and tautomers, N-oxides, and salts thereof, andsalts of tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which

-   R¹ represents a phenyl group, which is optionally substituted, one    or two times, each substituent independently selected from a    fluorine atom, a chlorine atom and a methyl group.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which

-   R¹ represents a C₄-C₈-cycloalkyl group or a    —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group which are optionally    substituted, one or two times, each substituent independently    selected from a halogen atom or a group selected from hydroxy,    phenyl and —N(R⁷)(R⁸),    -   wherein said phenyl substituent is optionally substituted, one,        two or three times, each substituent independently selected from        a halogen atom or a group selected from C₁-C₃-alkyl,        C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which

-   R¹ represents a 4- to 7-membered heterocycloalkyl group or a 5- to    7-membered heterocycloalkenyl group, wherein said 4- to 7-membered    heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group    are optionally substituted one or two times, each substituent    independently selected from a group selected from C₁-C₃-alkyl, 5- to    6-membered heteroaryl,-   —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl),    —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),    and wherein said 4- to 7-membered heterocycloalkyl group and 5- to    7-membered heterocycloalkenyl group are connected to the rest of the    molecule via a carbon atom of the said heterocycloalkyl- or    heterocyclalkenyl group.

In accordance with further embodiments, the present invention providescompounds of general formula (I), in which R¹ represents a indanylgroup, a tetralinyl group and a monocyclic—or bicyclic heteroaryl group

-   -   wherein said indanyl or tetralinyl group is optionally        substituted one or two times, each substituent independently        selected from a halogen atom or a group selected from        C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,        C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano, hydroxy and        —N(R⁷)(R⁸),    -   wherein said monocyclic or bicyclic heteroaryl group is        optionally substituted one, two or three times, each substituent        independently selected from a halogen atom or a group selected        from        C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,        C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano, hydroxy and        —N(R⁷)(R⁸) and tautomers, N-oxides, and salts thereof, and salts        of tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group,    -   a C₂-C₈-haloalkyl group,    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   and wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy                and hydroxy,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group,        -   wherein said 4-7-membered heterocycloalkyl group and said 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom, and which is            optionally substituted one or two times, each substituent            independently selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), hydroxy, C₁-C₆-hydroxyalkyl,            C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₆-alkyl)-, —SH, —S—(C₁-C₆-alkyl),            —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂,            —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or        -   wherein two vicinal substituents may form together a 5- or            6-membered, optionally heterocyclic, aromatic or            non-aromatic ring, having optionally 1-3 heteroatoms            independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,            and optionally containing a C(═O) group, and wherein the so            formed ring is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl), C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₄-C₈-cycloalkyl group, a        —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group, a 4-7-membered, optionally        unsaturated, heterocyclic group, a phenyl group, and a        monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4-7-membered, optionally unsaturated,            heterocyclic group is connected to the rest of the molecule            via a carbon atom,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            hydroxy, aryl, —O-aryl, cyano, —C(O)OH, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and            SF₅,        -   or wherein two vicinal substituents of said phenyl groups            may form together a 5- or 6-membered, optionally            heterocyclic, aromatic or non-aromatic ring, having            optionally 1-3 heteroatoms independently selected from —N═,            —NH—, —N(R⁷)—, —O—, —S—, and optionally containing a C(═O)            group, and wherein the so formed ring is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₈-alkyl group, a C₄-C₈-cycloalkyl group, a        —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4-7-membered, optionally unsaturated, heterocyclic group, a        phenyl group, and a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂ and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4-7-membered, optionally unsaturated,            heterocyclic group is connected to the rest of the molecule            via a carbon atom,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            hydroxy, aryl, —O-aryl, cyano, —C(O)OH, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂, —S(═O)(═NR¹¹)(C₁-C₃-alkyl),            —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or wherein two vicinal substituents of said phenyl groups            may form together a 5- or 6-membered, optionally            heterocyclic, aromatic or non-aromatic ring, having            optionally 1-3 heteroatoms independently selected from —N═,            —NH—, —N(R⁷)—, —O—, —S—, and optionally containing a C(═O)            group, and wherein the so formed ring is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂, —N(O)₂, and —N(R⁷)(R⁸)        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂, —N(O)₂,            and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.-   In further embodiments, the present invention provides compounds of    formula (I), supra, in which:-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from hydroxy, phenyl and —N(R⁷)(R⁸),            -   and wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy                and hydroxy,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4-7-membered heterocycloalkyl group a 5- to 7-membered        heterocycloalkenyl group, wherein said 4-7-membered        heterocycloalkyl group and said 5- to 7-membered        heterocycloalkenyl group are connected to the rest of the        molecule via a carbon atom, and which is optionally substituted        one or two times, each substituent independently selected from a        group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), hydroxy, C₁-C₆-hydroxyalkyl,            C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —O—C(═O)—(C₁-C₆-alkyl)-, —SH, —S—(C₁-C₆-alkyl),            —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂,            —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or        -   wherein two vicinal substituents may form together a 5- or            6-membered, optionally heterocyclic, aromatic or            non-aromatic ring, having optionally 1-3 heteroatoms            independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,            and optionally containing a C(═O) group, and wherein the so            formed ring is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl),            C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,            —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)        -   and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl),            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and            —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.-   In further embodiments, the present invention provides compounds of    formula (I), supra, in which-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said- to 7-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl- or heterocycloalkenyl group,    -   a 5- to 7-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and wherein said 5- to 7-membered heterocycloalkenyl group            is connected to the rest of the molecule via a carbon atom            of the said heterocycloalkyl- or heterocycloalkenyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl group, when they            are attached to adjacent ring atoms, are optionally linked            to one another in such a way that they jointly form a group            selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group, a tetralinyl group        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   and    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.-   In further embodiments, the present invention provides compounds of    formula (I), supra, in which-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group, a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 7-membered heterocycloalkyl group, a 5- to 7-membered        heterocycloalkenyl group, a phenyl group, an indanyl group, a        tetralinyl group and a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from C₁-C₃-alkyl, 5- to            6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl),            —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl),            —S(═O)₂(C₁-C₆-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl substituent is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 7-membered heterocycloalkyl group and 5-            to 7-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,            C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸),            —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.-   In further embodiments, the present invention provides compounds of    formula (I), supra, in which:-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,    -   a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom or            nitrogen atom of the said heterocycloalkyl- or            heterocycloalkenyl group,    -   a 5- to 6-membered heterocycloalkenyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   wherein said 5- to 6-membered heterocycloalkenyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl- or heterocycloalkenyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three, four or            five times, each substituent independently selected from a            halogen atom or a group selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,    -   an indanyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a tetralinyl group and        -   which is optionally substituted one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),    -   a monocyclic—or bicyclic heteroaryl group,        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group, a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group,    -   a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered        heterocycloalkenyl group a phenyl group, an indanyl group, a        tetralinyl group and a monocyclic—or bicyclic heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, each substituent independently selected            from a halogen atom or a group selected from        -   hydroxy, phenyl and —N(R⁷)(R⁸),            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and 5-            to 6-membered heterocycloalkenyl group are optionally            substituted one or two times, each substituent independently            selected from a group selected from        -   C₁-C₃-alkyl, 5- to 6-membered heteroaryl,            —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl),            —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O),            -   wherein said 5- to 6-membered heteroaryl group is                optionally substituted, one, two or three times, each                substituent independently selected from a halogen atom                or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group and 5-            to 6-membered heterocycloalkenyl group are connected to the            rest of the molecule via a carbon atom of the said            heterocycloalkyl- or heterocycloalkenyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three, four or five times, each substituent            independently selected from a halogen atom or a group            selected from        -   C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl,            C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,            C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶,            —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸),            —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅,        -   or in which two substituents of said phenyl groups, when            they are attached to adjacent ring atoms, are optionally            linked to one another in such a way that they jointly form a            group selected from        -   —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and            —NH—C(═O)—NH—,        -   and        -   wherein said indanyl- or tetralinyl group is optionally            substituted one or two times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl,            C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano,            hydroxy and —N(R⁷)(R⁸),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group,        -   which is optionally substituted, one or two times, with a            phenyl group, wherein said phenyl substituent is optionally            substituted, one, two or three times, each substituent            independently selected from a halogen atom,    -   a 4- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a C₁-C₃-alkyl group,        -   and        -   which is connected to the rest of the molecule via a carbon            atom of the said heterocycloalkyl group,    -   a phenyl group,        -   which is optionally substituted, one, two, three or four            times, each substituent independently selected from a            halogen atom or a group selected from C₁-C₄-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,    -   an indanyl group and    -   a monocyclic- or bicyclic heteroaryl group,        -   which are optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₄-C₈-cycloalkyl group, a 4- to 6-membered heterocycloalkyl        group,    -   a phenyl group, an indanyl group and a monocyclic- or bicyclic        heteroaryl group,        -   wherein said cycloalkyl groups are optionally substituted,            one or two times, with        -   a phenyl group,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            optionally substituted one or two times, each substituent            independently selected from a C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two, three or four times, each substituent independently            selected from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),            —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂,        -   and        -   wherein said monocyclic or bicyclic heteroaryl group is            optionally substituted one, two or three times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group, and        -   which is connected to the rest of the molecule via a carbon            atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸),            —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl),            —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl,            —S(═O)(═NH)(C₁-C₃-alkyl) and    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group, a 5- to 6-membered heterocycloalkyl        group,    -   a phenyl group, an indanyl group, and a monocyclic heteroaryl        group,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group,    -   a 5- to 6-membered heterocycloalkyl group,        -   which is optionally substituted one or two times, with a            C₁-C₃-alkyl group, and which is connected to the rest of the            molecule via a carbon atom,    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl,            —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and        -   —(C₁-C₃-alkyl)-N(R⁷)(R⁸),    -   an indanyl group, and    -   a monocyclic heteroaryl group,        -   which is optionally substituted one or two times, each            substituent independently selected from a group selected            from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸),            —N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl,            —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and            —(C₁-C₃-alkyl)-N(R⁷)(R⁸),            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In yet further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a phenyl group,        -   which is optionally substituted, one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl,            C₁-C₃-alkoxy, hydroxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In other embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a phenyl group,        -   which is optionally substituted, one or two times, each            substituent independently selected from a halogen atom or a            group selected from        -   C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In other embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a phenyl group,    -   which is optionally substituted, one or two times, each        substituent independently selected from a halogen atom        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   a C₅-C₇-cycloalkyl group, a 5- to 6-membered heterocycloalkyl        group, a phenyl group, an indanyl group, and a monocyclic        heteroaryl group,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuranyl, tetrahydro-2H-pyranyl and            piperidinyl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a C₁-C₃-alkyl group,        -   and        -   wherein said 5- to 6-membered heterocycloalkyl group is            connected to the rest of the molecule via a carbon atom of            the said heterocycloalkyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy,            —C(═O)OR⁶, —N(R⁷)(R⁸) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸),        -   and        -   wherein said monocyclic heteroaryl group is selected from            oxazolyl, pyrazolyl, pyridinyl and pyrimidinyl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times, each substituent independently selected            from a group selected from        -   C₁-C₃-alkyl and C₁-C₃-alkoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl,        -   and which is optionally substituted one or two times with a            methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each        -   substituent independently selected from a fluorine atom or a            chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, chinolinyl,            indazolyl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   cyclopentyl, cyclohexyl, cycloheptyl, 5- to 6-membered        heterocycloalkyl, phenyl, indan-2-yl and monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl            and piperidin-4-yl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃, amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazolyl, pyrazolyl, pyridinyl and pyrimidinyl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times,        -   each substituent independently selected from a group            selected from        -   methyl and methoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,        indan-2-yl,    -   a 5- to 6-membered heterocycloalkyl group, which is selected        from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and        piperidin-4-yl, and which is optionally substituted one or two        times with a methyl group,    -   a phenyl group, which is optionally substituted, one, two or        three times, each substituent independently selected from a        fluorine atom or a chlorine atom or a group selected from        -   methyl, ethyl, propyl, isopropyl, difluoromethyl,            trifluoromethyl,        -   methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃,            —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl,            —S—CH₃, —S(═O)₂CH₃,        -   and —S(═O)(NH)CH₃, and    -   a monocyclic heteroaryl group, which is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl,            pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            chinolin-5-yl, indazol-5-yl,        -   and which is optionally substituted one or two times, each            substituent independently selected from methyl and methoxy,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   cyclopentyl, cyclohexyl, cycloheptyl, 5- to 6-membered        heterocycloalkyl, phenyl, indan-2-yl and monocyclic heteroaryl,        -   wherein said 5- to 6-membered heterocycloalkyl group is            selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl            and piperidin-4-yl,        -   which 5- to 6-membered heterocycloalkyl group is optionally            substituted one or two times, with a methyl group,        -   and        -   wherein said phenyl groups are optionally substituted, one,            two or three times, each substituent independently selected            from a fluorine atom or a chlorine atom or a group selected            from        -   methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,            hydroxy, C(═O)OCH₃,        -   amino, methylamino and aminomethyl,        -   and        -   wherein said monocyclic heteroaryl group is selected from        -   oxazol-2-yl, pyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,            pyridin-4-yl, pyrimidin-2-yl and pyrimidin-4-yl,        -   which monocyclic heteroaryl group is optionally substituted            one or two times,        -   each substituent independently selected from a group            selected from        -   methyl and methoxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a hydrogen atom or a fluorine atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a hydrogen atom or a halogen atom,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a hydrogen atom or a fluorine atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a hydrogen atom, a fluorine atom or a chlorine atom,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a fluorine atom or a chlorine atom,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a fluorine atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R² represents a hydrogen atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),            —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₈-cycloalkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl),            C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,            C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy,            —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂, —N(O)₂,            and —N(R⁷)(R⁸)            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,    -   wherein said C₁-C₆-alkyl group is optionally substituted with a        C₃-C₈-cycloalkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is optionally substituted with a        C₁-C₃-alkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is connected to the alkyl group via a        carbon atom of the heterocycloalkyl group,    -   and    -   wherein said phenyl group is optionally substituted, one, two or        three times, each substituent independently selected from a        halogen atom or a group selected from    -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a        C₂-C₆-alkynyl group,    -   a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,    -   a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing        heterocycloalkyl) group and    -   a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a C₃-C₆-cycloalkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            C₁-C₃-alkyl group,        -   and        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is connected to the alkyl group via a            carbon atom of the heterocycloalkyl group,        -   and        -   wherein said phenyl group is optionally substituted, one,            two or three times, each substituent independently selected            from a halogen atom or a group selected from        -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a        -   C₃-C₆-cycloalkyl group,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group, a C₂-C₆-alkenyl group and a phenyl group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a cyclopropyl group,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₃-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group, and a C₂-C₃-alkenyl group        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₃-alkyl group, a C₁-C₃-haloalkyl group, and a        C₂-C₃-alkenyl group        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₃-alkyl group, and a C₁-C₃-haloalkyl group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₃-alkyl group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   a C₁-C₃-haloalkyl group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        trifluoromethyl, allyl, 2-methyl-prop1-enyl and phenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,                aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,                —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),                S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂,                and —N(R⁷)(R⁸)    -   a C₂-C₆-alkenyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₂-C₆-haloalkyl group,    -   a C₂-C₆-hydroxyalkyl group,    -   a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)NR⁷R⁸ group, and    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl,                cyano, —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl),                —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and                —N(R⁷)(R⁸)

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl,                cyano, —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl),                —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and                —N(R⁷)(R⁸)                or a tautomer, an N-oxide, a salt, a salt of a tautomer                or a salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,                C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,                -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,                C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl,                cyano, —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl),                —S—(C₂-C₆-alkenyl), —S(═O)₂, —N(O)₂, and —N(R⁷)(R⁸) and                tautomers, N-oxides, and salts thereof, and salts of                tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₈-cycloalkyl group, a        C₂-C₆-haloalkyl group,    -   a —C(═O)OR⁶ group, a C(═O)NR⁷R⁸ group, a        —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,                or a tautomer, an N-oxide, a salt, a salt of a tautomer                or a salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₈-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy,                and tautomers, N-oxides, and salts thereof, and salts of                tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₆-alkylenyl group, a C₃-C₆-cycloalkyl group, a        C₂-C₆-haloalkyl group,    -   a —C(═O)OR⁶ group, a C(═O)NR⁷R⁸ group, a        —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,    -   a C₂-C₆-hydroxyalkyl group and a —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl substituent is optionally                substituted, one, two or three times, each substituent                independently selected from a halogen atom or a group                selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy,                or a tautomer, an N-oxide, a salt, a salt of a tautomer                or a salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₂-C₆-haloalkyl        group,    -   a C₂-C₆-hydroxyalkyl group and a —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group,        -   wherein said C₁-C₆-alkyl group is optionally substituted            with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            -   wherein said phenyl group is optionally substituted,                one, two or three times, each substituent independently                selected from a halogen atom or a group selected from            -   C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy                and tautomers, N-oxides, and salts thereof, and salts of                tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₆-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group,    -   a —C(═O)OR⁶ group, a C(═O)NR⁷R⁸ group, a        —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,    -   a C₁-C₆-alkyl group,        -   which is optionally substituted with a group selected from            C₃-C₆-cycloalkyl and phenyl,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₆-hydroxyalkyl group, wherein said C₁-C₆-alkyl group is        optionally substituted with a group selected from        -   C₃-C₆-cycloalkyl and phenyl,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group, a —C(═O)OR⁶ group, a C(═O)NR⁷R⁸ group,        a —S(═O)(═NH)(C₁-C₃-alkyl) group,    -   a C₁-C₅-alkyl group,        -   which is optionally substituted with a group selected from        -   cyclopropyl and phenyl,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₅-alkyl group, a C₃-C₆-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₃-alkenyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group, a —C(═O)OR⁶ group, a C(═O)NR⁷R⁸ group,        a —S(═O)(═NH)(C₁-C₃-alkyl)group, and    -   a C₁-C₄-alkyl group,        -   said alkyl group is optionally substituted with a group            selected from cyclopropyl and phenyl,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₂-C₄-alkenyl group,    -   a C₃-C₅-cycloalkyl group,    -   a C₁-C₃-hydroxyalkyl group,    -   a C₁-C₄-alkyl group,        -   which is optionally substituted with a group selected from            cyclopropyl and phenyl,            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₁-C₃-hydroxyalkyl group,    -   wherein said C₁-C₄-alkyl group is optionally substituted with a        group selected from    -   cyclopropyl and phenyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group,        -   wherein said C₁-C₄-alkyl group is optionally substituted            with a group selected from        -   cyclopropyl and phenyl,            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a C₁-C₄-alkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl,        2-hydroxyethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl,        cyclopropylmethyl, 2-hydroxyethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   benzyl, cyclopropyl, cyclobutyl, cyclopentyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, cyclopropylmethyl,        benzyl, cyclopropyl, cyclopentyl and 2-hydroxyethyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   benzyl, cyclopropyl, cyclobutyl, cyclopentyl and —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —(C₁-C₆-alkyl)-O—(C₁-C₆-alkyl) group,    -   a C₂-C₆-alkenyl group,    -   a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group, and    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group,    -   a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group, and    -   a phenyl group        -   which is optionally substituted one, two or three times,            each substituent independently selected from a halogen atom            or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,            -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,            —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy,            aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH,            —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), S(═O)₂(C₁-C₆-alkyl),            —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸)            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy        group,    -   a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which: R⁵ represents a halogen atom or a groupselected from

-   -   a C₁-C₆-alkyl group,    -   a C₃-C₈-cycloalkyl group,    -   a C₁-C₆-haloalkyl group,    -   a C₁-C₆-hydroxyalkyl group, which is optionally substituted with        a hydroxy group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which: R⁵ represents a halogen atom or a groupselected from

-   -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group,    -   a C₁-C₆-alkoxy group,    -   a C₁-C₆-alkylsulfanyl group,    -   a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₆-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₆-hydroxyalkyl group,    -   a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group,    -   a C₁-C₆-alkoxy group,    -   C₁-C₆-alkylsulfanyl group,    -   —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl        group,    -   a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-        group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, a        —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group and    -   a —N(R⁷)(R⁸) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group,    -   a C₃-C₆-cycloalkyl group,    -   a C₁-C₃-haloalkyl group, which is optionally substituted with a        hydroxy group,    -   a C₁-C₃-hydroxyalkyl group,    -   (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)- group,    -   a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group,    -   a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group,    -   a —N(R⁷)(R⁸) group,    -   a —C(═O)OR⁶ group,    -   a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)-        group, a C₁-C₄-alkoxy group,    -   a C₁-C₃-alkylsulfanyl group, a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group        and a —N(R⁷)(R⁸) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group which is optionally substituted with a hydroxy group, a        C₁-C₃-hydroxyalkyl group, a CH₃O—(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group, a methylsulfanyl group, a        —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a —N(R⁷)(R⁸) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a methoxy-(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group, a methylsulfanyl group, a        —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a —N(R⁷)(R⁸) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, hydroxy(trifluoromethyl)methyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-chloroethyl,        1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl, methoxy,        isopropoxy, methylsulfanyl, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino, —C(═O)OH,    -   —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHcyclopropyl,        —C(═O)N(CH₃)₂, and —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        1-methoxyethyl, methoxy, isopropoxy, methylsulfanyl,        aminomethyl, (methylamino)methyl, (dimethylamino)methyl,        1-aminoethyl, 2-aminoethyl, methylamino and ethyl(methyl)amino,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl,        hydroxymethyl, hydroxy(trifluoromethyl)methyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-methoxyethyl, methoxy, isopropoxy,        methylsulfanyl, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃,        —C(═O)NHcyclopropyl, —C(═O)N(CH₃)₂, and —S(═O)(═NH)CH₃,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        trifluoromethyl, hydroxymethyl, hydroxy(trifluoromethyl)methyl,        1-hydroxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, methoxy,        isopropoxy, aminomethyl, (methylamino)methyl,        (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino        and ethyl(methyl)amino,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        trifluoromethyl, hydroxymethyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-methoxyethyl, methoxy, isopropoxy        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   trifluoromethyl, hydroxymethyl, 1-hydroxyethyl,        2-hydroxypropan-2-yl, 1-methoxyethyl, methoxy, isopropoxy        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   methyl, ethyl, propyl, isopropyl, 2-butyl, tert-butyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   trifluoromethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        1-methoxyethyl, methoxy, isopropoxy        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and C₁-C₃-alkoxy-(C₁-C₃)alkyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   C₁-C₅-hydroxyalkyl and C₁-C₅-alkoxy,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₅-hydroxyalkyl group    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   C₁-C₄-hydroxyalkyl and C₁-C₄-alkoxy,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₄-hydroxyalky group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₄-alkoxy group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   C₁-C₃-hydroxyalkyl and C₁-C₃-alkoxy,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₃-hydroxyalkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   hydroxymethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   1-hydroxyethyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   2-hydroxypropan-2-yl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a group selected from    -   1-methoxyethyl, methoxy, isopropoxy        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₆-alkyl group and a benzyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁶ represents a hydrogen atom or a group selected from    -   a C₁-C₄-alkyl group and a benzyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁶ represents a hydrogen atom or a methyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        C₃-C₆-cycloalkyl group, and a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 7-membered heterocycloalkyl    group,    -   which is optionally substituted with a group selected from    -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,-   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a        C₃-C₆-cycloalkyl group, and a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group and a        —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        -   wherein said 4- to 7-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group,    -   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),            or a tautomer, an N-oxide, a salt, a salt of a tautomer or a            salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group and a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group,-   or-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from    -   a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group and a        —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        -   wherein said 4- to 6-membered nitrogen containing            heterocycloalkyl group is optionally substituted with a            group selected from        -   C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl),            and tautomers, N-oxides, and salts thereof, and salts of            tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group or a cyclopropyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,-   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen    atom or    -   a C₁-C₃-alkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 7-membered heterocycloalkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or aC₁-C₃-alkyl group,

or

R⁹ and R¹⁰ together with the nitrogen to which they are attachedrepresent a

-   -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a    -   nitrogen containing 4- to 6-membered heterocycloalkyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹¹ represents a hydrogen atom or a group selected from    -   a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹¹ represents a hydrogen atom,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (Ia),

in whichR²-R¹¹ have the meanings as in any of claims 1-6 unless specified belowand R* and R** are independently selected from a halogen atom or a groupselected from C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,-aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,—O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, hydroxy, aryl,—O-aryl, cyano, —C(O)OH, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸),—(C₁-C₆-alkyl)-N(R⁷)(R⁸), —(C₁-C₆-alkyl)-C(═O)OR⁶,—(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH, —S—(C₁-C₆-alkyl),—S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂N(R⁷)(R⁸),—S(═O)₂(C₁-C₃-alkyl),—S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and SF₅,or wherein, in case R* and R** do have vicinal position in the phenylgroup, they may form together a 5- or 6-membered, optionallyheterocyclic, aromatic or non-aromatic ring, having optionally 1-3heteroatoms independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,and optionally containing a C(═O) group, and wherein the so formed ringis optionally substituted one or two times, each substituentindependently selected from a halogen atom or a group selected fromC₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl,—(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,—C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl),—S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸)andR³ represents a group selected froma C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group,a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynylgroup,a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl)group anda phenyl group,

-   -   wherein said C₁-C₆-alkyl group is optionally substituted with a    -   C₃-C₈-cycloalkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is optionally substituted with a        C₁-C₃-alkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is connected to the alkyl group via a        carbon atom of the heterocycloalkyl group,    -   and    -   wherein said phenyl group is optionally substituted, one, two or        three times, each substituent independently selected from a        halogen atom or a group selected from C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl,        —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,        C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,        C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,        —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl),        —N(O)₂, and —N(R⁷)(R⁸),        more specifically R³ representing a C₁-C₆-alkyl group, a        C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₂-C₆-alkenyl        group, a phenyl group which is optionally substituted with a        C₃-C₈-cycloalkyl group, even further more specifically R³        represents a CF₃ group,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (Ia),

in whichR²-R¹¹ have the meanings as in claim 1 unless specified belowand R* and R** are independently selected from a halogen atom or a groupselected from C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl,-aryl-(C₁-C₆-alkyl), C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,—O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, hydroxy, aryl,—O-aryl, cyano, —C(O)OH, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸),—(C₁-C₆-alkyl)-N(R⁷)(R⁸), —(C₁-C₆-alkyl)-C(═O)OR⁶,—(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —SH, —S—(C₁-C₆-alkyl),—S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl),—S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and SF₅,or wherein, in case R* and R** do have vicinal position in the phenylgroup, they may form together a 5- or 6-membered, optionallyheterocyclic, aromatic or non-aromatic ring, having optionally 1-3heteroatoms independently selected from —N═, —NH—, —N(R⁷)—, —O—, —S—,and optionally containing a C(═O) group, and wherein the so formed ringis optionally substituted one or two times, each substituentindependently selected from a halogen atom or a group selected fromC₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl,—(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano,—C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —N(O)₂, and—N(R⁷)(R⁸)andR³ represents a group selected froma C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group,a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynylgroup,a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group,a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl)group anda phenyl group,

-   -   wherein said C₁-C₆-alkyl group is optionally substituted with a        C₃-C₈-cycloalkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is optionally substituted with a        C₁-C₃-alkyl group,    -   and    -   wherein said 4- to 7-membered nitrogen containing        heterocycloalkyl group is connected to the alkyl group via a        carbon atom of the heterocycloalkyl group,    -   and    -   wherein said phenyl group is optionally substituted, one, two or        three times, each substituent independently selected from a        halogen atom or a group selected from C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl,        —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl,        C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy,        C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH,        —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸),        more specifically R³ representing a C₁-C₆-alkyl group, a        C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₂-C₆-alkenyl        group, a phenyl group which is optionally substituted with a        C₃-C₈-cycloalkyl group, even further more specifically R³        represents a CF₃ group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group,    which phenyl group is optionally substituted, one or two times, each    substituent independently selected from a halogen atom, a    C₁-C₃-alkyl group, a trifluoromethyl group, a amino group or a    —NH(C₁-C₃-alkyl) group, or more specifically selected from a    fluorine atom, a chlorine atom, a methyl group, a ethyl group, a    propyl group, a propan-2-yl group, a trifluoromethyl group, a amino    group, a —NH(CH₃) group, or even more specifically selected from a    fluorine atom, a chlorine atom and a methyl group,    and-   R³ represents a trifluoromethyl group and tautomers, N-oxides, and    salts thereof, and salts of tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group,    which phenyl group is optionally substituted, one or two times, each    substituent independently selected from a halogen atom, a    C₁-C₃-alkyl group, a trifluoromethyl group, a amino group or a    —NH(C₁-C₃-alkyl) group, or more specifically selected from a    fluorine atom, a chlorine atom, a methyl group, a ethyl group, a    propyl group, a propan-2-yl group, a trifluoromethyl group, a amino    group, a —NH(CH₃) group, or even more specifically selected from a    fluorine atom, a chlorine atom and a methyl group,    and-   R² represents a hydrogen atom or a fluorine atom and tautomers,    N-oxides, and salts thereof, and salts of tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group,    which phenyl group is optionally substituted, one or two times, each    substituent independently selected from a halogen atom, a    C₁-C₃-alkyl group, a trifluoromethyl group, a amino group or a    —NH(C₁-C₃-alkyl) group, or more specifically selected from a    fluorine atom, a chlorine atom, a methyl group, a ethyl group, a    propyl group, a propan-2-yl group, a trifluoromethyl group, a amino    group, a —NH(CH₃) group, or even more specifically selected from a    fluorine atom, a chlorine atom and a methyl group,    and-   R² represents a fluorine atom and tautomers, N-oxides, and salts    thereof, and salts of tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group, which is optionally substituted, one    or two times, each substituent independently selected from a halogen    atom, a C₁-C₃-alkyl group, a trifluoromethyl group, or more    specifically selected from a fluorine atom, a chlorine atom, a    methyl group, a ethyl group, a propyl group, a propan-2-yl group, a    trifluoromethyl group,-   R² represents a hydrogen atom, a fluorine atom, or a chlorine atom,    more specifically a hydrogen atom or a fluorine atom,-   R³ represents a group selected from propyl, 2-methylpropyl,    3-pentyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, difluormethyl, trifluoromethyl, allyl,    2-methyl-prop-1-enyl-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₅-cycloalkyl group and a        C₂-C₃-hydroxyalkyl group, wherein said C₁-C₄-alkyl group is        optionally substituted with a group selected from cyclopropyl        and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a CH₃O—(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group and a        —N(R⁷)(R⁸) group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group, which is optionally substituted, one,    two or three times, each substituent independently selected from a    halogen atom, a hydroxy group, a C₁-C₃-alkyl group, a    trifluoromethyl group, or more specifically selected from a hydroxy    group, a fluorine atom, a chlorine atom, a methyl group, a ethyl    group, a propyl group, a propan-2-yl group, a trifluoromethyl group,-   R² represents a hydrogen atom, a fluorine atom, or a chlorine atom,    more specifically a hydrogen atom or a fluorine atom,-   R³ represents a group selected from propyl, 2-methylpropyl,    3-pentyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, difluormethyl, trifluoromethyl, allyl,    2-methyl-prop-1-enyl-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₂-C₃-alkenyl group, a C₃-C₅-cycloalkyl        group and a C₂-C₃-hydroxyalkyl group,    -   wherein said C₁-C₄-alkyl group is optionally substituted with a        group selected from cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a CH₃O—(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group, a        —N(R⁷)(R⁸) group, a C(═O)OR⁶ group and a C(═O)NR⁷R⁸ group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group, which is optionally substituted, one,    two or three times, each substituent independently selected from a    hydroxy group, a fluorine atom, a chlorine atom, a methyl group, a    ethyl group, a propyl group, a propan-2-yl group, a trifluoromethyl    group,-   R² represents a hydrogen atom or a fluorine atom,-   R³ represents a group selected from propyl, 2-methylpropyl,    3-pentyl, difluormethyl, trifluoromethyl, allyl,    2-methyl-prop-1-enyl-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₂-C₃-alkenyl group, a C₃-C₅-cycloalkyl        group and a C₂-C₃-hydroxyalkyl group, wherein said C₁-C₄-alkyl        group is optionally substituted with a group selected from        cyclopropyl and phenyl,-   R⁵ represents a halogen atom or a group selected from    -   a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl        group,    -   a C₁-C₃-hydroxyalkyl group, a CH₃O—(C₁-C₂-alkyl)- group, a        C₁-C₃-alkoxy group,    -   a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group, a        —N(R⁷)(R⁸) group, a C(═O)OR⁶ group and a C(═O)NR⁷R⁸ group,-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group, which is optionally substituted, one,    two or three times, each substituent independently selected from a    hydroxy group, a fluorine atom, a chlorine atom, a methyl group,-   R² represents a fluorine atom,-   R³ represents a trifluoromethyl group,-   R⁴ represents a group selected from methyl, ethyl, propyl, and    isopropyl,-   R⁵ represents a group selected from methyl, hydroxymethyl,    hydroxyethyl, hydroxypropyl, a C(═O)OR⁶ group and a C(═O)NR⁷R⁸ group-   R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group, which is optionally substituted, one    or two times, each substituent independently selected from a    fluorine atom, a chlorine atom, a methyl group,-   R² represents a fluorine atom,-   R³ represents a trifluoromethyl group,-   R⁴ represents a group selected from methyl, ethyl, propyl,    isopropyl,-   R⁵ represents a group selected from methyl, hydroxymethyl,    hydroxyethyl, hydroxypropyl,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a group selected from    -   C₃-C₆-alkyl, C₅-C₆-cycloalkyl, a pyridyl group which is        substituted with methyl and/or methoxy, or phenyl which is        substituted one or more times with a group independently        selected from fluorine atom, a chlorine atom, a C₁-C₃-alkyl        group, a trifluoromethyl group, a amino group or a        —NH(C₁-C₃-alkyl) group.-   R² represents a fluorine atom,-   R³ represents a group selected from    -   a propyl group, a cyclobutyl group, a trifluoromethyl group, a        allyl group and a phenyl group,-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group and a cyclopropyl group,-   R⁵ represents a chlorine atom or a group selected from    -   C₁-C₃-alkyl, C₄-C₆-cycloalkyl, trifluoromethyl,        C₁-C₃-hydroxyalkyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a group selected from    -   3-pentyl, cycloheptyl, 2-methoxy-4-methylpyridin-3-yl,        2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl,        2-fluoro-6-methylphenyl, 4-fluoro-2-methylphenyl,        2-methylphenyl, 2-ethylphenyl, 2-propylphenyl,        2-(propan-2-yl)phenyl, 2-(trifluoromethyl)phenyl,        2-(methylamino)phenyl and 3-amino-2-methylphenyl,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl, cyclobutyl, trifluoromethyl, allyl and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl and cyclopropyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,        trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a group selected from    -   2,6-dichlorophenyl, 2-chloro-6-fluorophenyl,        2-fluoro-6-methylphenyl and 2-methylphenyl,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a group selected from    -   2,6-dichlorophenyl, 2-chloro-6-fluorophenyl,        2-fluoro-6-methylphenyl, 2,6-difluorophenyl,        2-chloro-6-fluoro-5-hydroxyphenyl,        2-chloro-6-fluoro-4-hydroxyphenyl,        2-chloro-6-fluoro-3-hydroxyphenyl,        2-chloro-6-fluoro-3-methoxyphenyl and 2-methylphenyl,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, 2-propenyl and cyclobutyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl, COOH, CONR⁷R⁸, and-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group-   R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or    a C₁-C₃-alkyl group,    -   or-   R⁹ and R¹⁰ together with the nitrogen to which they are attached    represent a nitrogen containing 4- to 6-membered heterocycloalkyl    group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I),

in which

-   R¹ represents a phenyl group which is optionally substituted, one,    two or three times, each substituent independently selected from a    halogen atom, a C₁-C₃-alkyl group and a C₁-C₃-alkoxy group,-   R² represents a fluorine or chlorine atom,-   R³ represents a group selected from    -   C₁-C₄-alkyl group or a C₁-C₄-haloalkyl group,-   R⁴ represents a group selected from    -   a C₁-C₄-alkyl group, a C₂-C₃-alkenyl group and a        C₄-C₅-cycloalkyl group-   R⁵ represents a chlorine atom or a group selected from    -   C₁-C₄-alkyl group, C₃-C₅ cycloalkyl group, cyclopropyl,        C₁-C₄-hydroxyalkyl group, COOH, and CONR⁷R⁸,-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I),

in which

-   R¹ represents a phenyl group which is optionally substituted, one,    two or three times, each substituent independently selected from a    fluorine atom, a chlorine atom, a methyl group and a methoxy group,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, 2-propenyl and cyclobutyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl, COOH, CONR⁷R⁸, and-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a group selected from a C₁-C₃-alkyl group, a    C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and    C₃-C₆-cycloalkyl group    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I),

in which

-   R¹ represents a phenyl group which is optionally substituted, one,    two or three times, each substituent independently selected from a    fluorine atom, a chlorine atom, a methyl group and a methoxy group,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, 2-propenyl and cyclobutyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl, COOH, CONR⁷R⁸, and-   R⁷ and R⁸ represent, independently for each occurrence, a hydrogen    atom or a C₁-C₃-alkyl group    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group,    -   which phenyl group is optionally substituted, one or two times,        each substituent independently selected from a fluorine atom, a        chlorine atom and a methyl group,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a phenyl group,    -   which phenyl group is optionally substituted, one or two times,        each substituent independently selected from a fluorine atom, a        chlorine atom and a methyl group,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl and C₁-C₃-hydroxyalkyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I),

in which

-   R¹ represents a phenyl group,    -   which phenyl group is optionally substituted, one or two times,        each substituent independently selected from a hydroxy group, a        fluorine atom, a chlorine atom and a methyl group,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl and C₁-C₃-hydroxyalkyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providesthe compounds of general formula (I),

in which

-   R¹ represents a phenyl group,    -   which phenyl group is optionally substituted, one or two times,        each substituent independently selected from a hydroxy group, a        fluorine atom, a chlorine atom and a methyl group,-   R² represents a fluorine atom or a chlorine atom,-   R³ represents a group selected from    -   propyl and trifluoromethyl,-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl and C₁-C₃-hydroxyalkyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

in which

-   R¹ represents a group selected from    -   cycloheptyl, 2-methoxy-4-methylpyridin-3-yl, 2,6-dichlorophenyl,        2-chloro-6-fluorophenyl, 2,6-difluorophenyl,        2-fluoro-6-methylphenyl, 4-fluoro-2-methylphenyl,        2-methylphenyl, 2-ethylphenyl, 2-propylphenyl,        2-(propan-2-yl)phenyl, 2-(trifluoromethyl)phenyl,        2-(methylamino)phenyl and 3-amino-2-methylphenyl,-   R² represents a fluorine atom,-   R³ represents a group selected from    -   propyl, trifluoromethyl, allyl and phenyl,-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl and cyclopropyl,-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,        trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   3-pentyl, cycloheptyl, 2-methoxy-4-methylpyridin-3-yl,        2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl,        2-fluoro-6-methylphenyl, 4-fluoro-2-methylphenyl,        2-methylphenyl, 2-ethylphenyl, 2-propylphenyl,        2-(propan-2-yl)phenyl, 2-(trifluoromethyl)phenyl,        2-(methylamino)phenyl and 3-amino-2-methylphenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In accordance with further embodiments, the present invention providescompounds of general formula (I),

-   R¹ represents a group selected from    -   cycloheptyl, 2-methoxy-4-methylpyridin-3-yl, 2,6-dichlorophenyl,        2-chloro-6-fluorophenyl, 2,6-difluorophenyl,        2-fluoro-6-methylphenyl, 4-fluoro-2-methylphenyl,        2-methylphenyl, 2-ethylphenyl, 2-propylphenyl,        2-(propan-2-yl)phenyl, 2-(trifluoromethyl)phenyl,        2-(methylamino)phenyl and 3-amino-2-methylphenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   propyl, cyclobutyl, trifluoromethyl, allyl and phenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.-   R³ represents a group selected from    -   propyl, trifluoromethyl, allyl and phenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl, propyl, isopropyl and cyclopropyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,        trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a phenyl group,    -   which phenyl group is optionally substituted, one or two times,        each substituent independently selected from a fluorine atom, a        chlorine atom and a methyl group,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R¹ represents a group selected from    -   2,6-dichlorophenyl, 2-chloro-6-fluorophenyl,        2-fluoro-6-methylphenyl and 2-methylphenyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   propyl and trifluoromethyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents a group selected from    -   propyl,        or a tautomer, an N-oxide, a salt, a salt of a tautomer or a        salt of an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R³ represents trifluoromethyl group,    or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of    an N-oxide thereof.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁴ represents a group selected from    -   methyl, ethyl and propyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl and C₁-C₃-hydroxyalkyl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₅-hydroxyalkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₄-hydroxyalkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a C₁-C₃-hydroxyalkyl group,    and tautomers, N-oxides, and salts thereof, and salts of tautomers    or N-oxides.

In further embodiments, the present invention provides compounds offormula (I), supra, in which:

-   R⁵ represents a chlorine atom or a group selected from    -   ethyl, isopropyl, cyclopropyl, hydroxymethyl, 1-hydroxyethyl and        2-hydroxypropan-2-yl,        and tautomers, N-oxides, and salts thereof, and salts of        tautomers or N-oxides.

The present invention provides any sub-combination within any embodimentor aspect of the present invention of compounds of general formula (I),supra.

The present invention provides any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformulae (IV), (VI), (VIII), (IX), (X), (XV), (XVIII), (XIX), (X) and(XXI).

The present invention provides the compounds of general formula (I)which are disclosed in the Example Section of this text, infra.

The compounds according to the invention of general formula (I) can beprepared according to the following schemes 1, 2, 3, 4 and 5. Theschemes and procedures described below illustrate synthetic routes tothe compounds of general formula (I) of the invention and are notintended to be limiting. It is clear to the person skilled in the artthat the order of transformations as exemplified in schemes 1, 2, 3, 4and 5 can be modified in various ways. The order of transformationsexemplified in these schemes is therefore not intended to be limiting.In addition, interconversion of any of the substituents, R¹, R², R³, R⁴or R⁵ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3^(rd) edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

Synthetic Routes

Five routes for the preparation of compounds of general formula (I) aredescribed in schemes 1, 2, 3, 4 and 5.

Scheme 1:

Route for the preparation of compounds of general formula (I) in whichR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I),supra.

Compounds of general formulae (II), (IV), (VI) and (X) are eithercommercially available or can be prepared according to proceduresavailable from the public domain, as understandable to the personskilled in the art. Specific examples are described in the ExperimentalSection.(II)→(III):

tert-Butyl benzoates of general formula (II) can be prepared frombenzoic acid derivatives of general formula (II) according to proceduresavailable from the public domain, as understandable to the personskilled in the art.

In connection with the method of the invention, the use ofdi-tert-butyl-dicarbonate in tert-butanol was preferable.

Alternatively, the tert-butyl benzoates of general formula (III) can beprepared from benzoic acid derivatives of general formula (II) by insitu formation of the corresponding acid chlorides and subsequentreaction with tert-butanol.

In situ formation of acid chlorides from benzoic acids of generalformular (II) can be accomplished, for example by using oxalyl chlorideor thionyl chloride, both reagents used in the presence of catalyticamount of N,N-dimethylformamide.(III)+(IV)→(V):The formation of tert-butyl benzoates of general formula (V) can beaccomplished by the reaction of triazolinones of general formula (IV)with tert-butyl benzoates of general formula (III) in the presence of abase. In connection with the method of the invention, the use of1,8-diazabicyclo[5.4.0]undec-7-ene as organic base in acetonitrile at80° C. was preferable.(V)+(VI)→(VII)→(VIII):The formation of benzoic acids of general formula (VIII) can beaccomplished by reaction of tert-butyl benzoates of general formula (V)with alcohols of general formula (VI) in the presence of a base, andsubsequent saponification of the resulting ester of general formula(VII).

Bases that can be employed for the reaction of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are forexample sodium hydride, sodium tert-butanolate, potassiumtert-butanolate, or cesium carbonate. In connection with the method ofthe invention, potassium hexamethyldisilazide solution intetrahydrofuran was preferrably used as organic base.

Solvents that can be used for the reactions of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are forexample tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide.In connection with the method according to the invention tertahydrofuranwas preferrably used as solvent.

Reaction temperatures for the reactions of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are forexample ranging from room temperature to 130° C. Cooling of the reactionmixture is optionally necessary on adding the reactants or bases. Inconnection with the method of the invention, cooling the reaction to−10° C. prior addition of potassium hexamethyldisilazide solution intetrahydrofuran and subsequent running the reaction at room temperaturewas preferable.

Suitable reaction times for the reaction of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are rangingfrom 1 h several days.

The reaction of tert-butyl benzoates of general formula (V) withalcohols of general formula (VI) can also result in transesterification,such as the tert-butoxide moiety of the tert-butyl benzoates of generalformula (V) can be replaced by the alkoxide R³CH(CH₃)O moiety of thealcohols of general formula (VI). In order to obtain the benzoic acidsof general formula (VIII), subsequent ester hydrolysis is required.

Ester hydrolysis can be achieved by various methods which are well knownto the person skilled in the art, for example by treatment of the esterswith lithium hydroxide, sodium hydroxide or potassium hydroxide, insolvents, such as, for example water, 1,4-dioxane, ethanol ortetrahydrofuran or mixtures thereof. The reactions can be carried out attemperatures ranging from room temperature to the boiling point of therespective solvent or solvent mixture.

In connection with the method of the invention, use of lithium hydroxidein water/dioxane was preferable.(VIII)→(IX),(VIII)/((IX)+(X)→(I):The compounds of general formula (I) can be prepared by the reaction ofthe benzoic acids of general formula (VIII) with amines of generalformula (X) either by

-   -   in situ formation of the corresponding acid chlorides of general        formula (IX) and subsequent reaction with amines of general        formula (X),        or by    -   amide coupling of the benzoic acids of general formula (VIII)        with amines of general formula (X).

In situ formation of acid chlorides of general formula (IX) from benzoicacids of general formular (VIII) can be accomplished, for example byusing oxalyl chloride or thionyl chloride, both reagents used in thepresence of catalytic amount of N,N-dimethylformamide. In connectionwith the method according to the invention, oxalyl chloride ispreferably used in the presence of N,N-dimethylformamide.

Suitable solvents for the in situ formation of acid chlorides of generalformula (IX) from benzoic acids of general formula (VIII) includeaprotic nonpolar solvents such as for example dichloromethane ortoluene. In connection with the method according to the invention,dichloromethane is preferably used as solvent.

Suitable reaction temperatures for the in situ formation of acidchlorides of general formula (IX) from benzoic acids of general formula(VIII) mostly reflect the boiling point of the solvents used in thereaction. In connection with the method according to the invention,adding of oxalyl chloride was carried out at 0° C. and the reactionmixture was subsequently allowed to warm up to room temperature.

Subsequent reactions of the in situ formed acid chlorides of generalformula (IX) with amines of general formula (X) can be carried out inthe presence of an organic base. Suitable organic bases are for exampletriethylamine, pyridine or N-ethyl-N,N-diisopropylamine. In connectionwith the method according to the invention, triethylamine was preferablyused as organic base.

Suitable solvents for the reaction of acid chlorides of general formula(IX) with amines of general formula (X) include aprotic polar solventssuch as for example acetonitrile, N,N-dimethylformamide or aproticnonpolar solvents such as dichloromethane. In connection with the methodaccording to the invention dichloromethane was used as solvent.

Suitable coupling reagents for the reaction of benzoic acids of generalformula (VIII) with amines of general formula (X) are for exampleO-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide or a combination of1H-benzotria-1-ol and 1-ethyl-3-[3-(diemthylaminopropyl]carbodiimidehydrochloride.

Suitable organic bases for the amide coupling of benzoic acids ofgeneral formula (VIII) with amines of general formula (X) are forexample 4-(dimethylamino)pyridine, N-ethyl-N,N-diisopropylamine ortriethylamine.

Suitable solvents for the for the amide coupling of benzoic acids ofgeneral formula (VIII) with amines of general formula (X) are forexample N,N-dimethylformamide, dichoromethane or tetrahydrofuran.

For coupling of the amide bond, other methods which are well known tothe person skilled in the art are also suitable, such as a condensationbetween amine and acid using propanephosphonic acid anhydride (T3P) ascoupling reagent.

In connection with the invention, formation of the compounds accordingto the invention of general formula (I) were preferrably accomplished byin situ formation of acid chlorides of general formula (IX) from benzoicacids of general formula (VIII) and subsequent reaction with amines ofgeneral formula (X).

Scheme 2:

Route for the preparation of compounds of general formula (I) in whichR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I),supra, and A represents a chlorine, bromine or iodine atom.

Compounds of general formulae (XI), (IV), (VI) and (X) are eithercommercially available or can be prepared according to proceduresavailable from the public domain, as understandable to the personskilled in the art. Specific examples are described in the ExperimentalSection.(XI)+(VI)→(XII):

Nitriles of general formula (XII) can be prepared from nitriles ofgeneral formula (XI) and with alcohols of general formula (VI) accordingto procedures available from the public domain, as understandable to theperson skilled in the art.

In connection with the method of the invention, the use of sodiumhydride in DMF was preferable.

Alternatively, for alcohols of sufficiently high acidity the use ofpotassium carbonate was preferable.(XII)→(XIII):

The formation of benzoates of general formula (XIII) can be accomplishedby hydrolysis of nitriles of general formula XII using strong acids orbases.

In connection with the method of the invention, the use of sodiumhydroxide in ethanol at 90° C. was preferable.(XIII)→(XIV)+(X)→(XV):

The compounds of general formula (XV) can be prepared by the reaction ofthe benzoic acids of general formula (XIII) with amines of generalformula (X) either by

-   -   in situ formation of the corresponding acid chlorides of general        formula (XIV) and subsequent reaction with amines of general        formula (X),        or by    -   amide coupling of the benzoic acids of general formula (XV) with        amines of general formula (X).

In situ formation of acid chlorides of general formula (XIV) frombenzoic acids of general formular (XIII) can be accomplished, forexample by using oxalyl chloride or thionyl chloride, both reagents usedin the presence of catalytic amount of N,N-dimethylformamide. Inconnection with the method according to the invention, oxalyl chlorideis preferably used in the presence of N,N-dimethylformamide.

Suitable solvents for the in situ formation of acid chlorides of generalformula (XIV) from benzoic acids of general formula (XIII) includeaprotic nonpolar solvents such as for example dichloromethane ortoluene. In connection with the method according to the invention,dichloromethane is preferably used as solvent.

Suitable reaction temperatures for the in situ formation of acidchlorides of general formula (XIV) from benzoic acids of general formula(XIII) mostly reflect the boiling point of the solvents used in thereaction. In connection with the method according to the invention,adding of oxalyl chloride was carried out at 0° C. and the reactionmixture was subsequently allowed to warm up to room temperature.

Subsequent reactions of the in situ formed acid chlorides of generalformula (XIV) with amines of general formula (X) can be carried out inthe presence of an organic base. Suitable organic bases are for exampletriethylamine, pyridine or N-ethyl-N,N-diisopropylamine. In connectionwith the method according to the invention, triethylamine was preferablyused as organic base.

Suitable solvents for the reaction of acid chlorides of general formula(XIV) with amines of general formula (X) include aprotic polar solventssuch as for example acetonitrile, N,N-dimethylformamide or aproticnonpolar solvents such as dichloromethane. In connection with the methodaccording to the invention dichoromethane was used as solvent.

Suitable coupling reagents for the reaction of benzoic acids of generalformula (XIII) with amines of general formula (X) are for exampleO-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide or a combination of1H-benzotria-1-ol and 1-ethyl-3-[3-(diemthylaminopropyl]carbodiimidehydrochloride.

Suitable organic bases for the amide coupling of benzoic acids ofgeneral formula (XIII) with amines of general formula (X) are forexample 4-(dimethylamino)pyridine, N-ethyl-N,N-diisopropylamine ortriethylamine.

Suitable solvents for the for the amide coupling of benzoic acids ofgeneral formula (XIII) with amines of general formula (X) are forexample N,N-dimethylformamide, dichoromethane or tetrahydrofuran.

For coupling of the amide bond, other methods which are well known tothe person skilled in the art are also suitable, such as a condensationbetween amine and acid using propanephosphonic acid anhydride (T3P) ascoupling reagent.

In connection with the invention, formation of the compounds accordingto the invention of general formula (XV) were preferrably accomplishedby in situ formation of acid chlorides of general formula (XIV) frombenzoic acids of general formula (XIII) and subsequent reaction withamines of general formula (X).(XV)+(IV)→(I):

Compounds according to the invention of general formula (I) can beprepared from halides of general formula (XV) and from triazolones ofgeneral formula (IV) using transition metals as catalysts.

Intermediates of general formula (XV) can be reacted with a suitabletriazolone of general formula (IV), such as, for example3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one, in the presence of asuitable base, such as, for example cesium carbonate, and a suitablepalladium catalyst, such as for example(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium, in the presence of asuitable ligand, such as for example(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), in a suitablesolvent system, such as, for example, dioxane, in a temperature rangefrom room temperature to the boiling point of the respective solvent,preferably the reaction is carried out at 100° C. to furnish compoundsof general formula (I). Alternatively the following palladium catalystscan be used:

allylpalladium chloride dimer, dichlorobis(benzonitrile)palladium (II),palladium (II) acetate, palladium (II) chloride,tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0),chloro(2′-amino-1,1′-biphenyl-2-yl)palladium(II) dimer,(2′-amino-1,1′-biphenyl-2-yl)methanesulfonatopalladium(II) dimer,trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)[cataCXium® C],allylchloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]palladium(II),allylchloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II),chloro[(1,3-dimesitylimidazol-[1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene](chloro){2-[(dimethylamino)methyl]phenyl}palladium,chloro[(1,2,3-N)-3-phenyl-2-propenyl][1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(II),[2-(acetylamino)phenyl]{1,3-bis[2,6-di(propan-2-yl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene}chloropalladium,{1,3-bis[2,6-di(propan-2-yl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene}(chloro){2-[(dimethylamino)methyl]phenyl}palladium,{1,3-bis[2,6-di(propan-2-yl)phenyl]-2,3-dihydro-1H-imidazol-2-yl}(dichloro)(3-chloropyridine-kappaN)palladium,[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride,[2-(acetylamino)-4-methoxyphenyl]{1,3-bis[2,6-di(propan-2-yl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene}chloropalladium,{1,3-bis[2,6-di(propan-2-yl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene}(chloro){2-[(dimethylamino)methyl]-3,5-dimethoxyphenyl}palladium,dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), dichloro(di-p-chloro)bis[1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]dipalladium(II),2-(2′-di-tert-butylphosphine)biphenylpalladium(II) acetate,chloro[dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)-lambda5-phosphanyl][2-(phenyl-kappaC2)ethanaminato-kappaN]palladium,[2-(2-aminoethyl)phenyl](chloro)palladium-di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,{dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane}{2-[2-(methylazanidyl-kappaN)ethyl]phenyl-kappaC1}palladium,chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II),[2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane-[2-(2-aminoethyl)phenyl](chloro)palladium,[2-(2-aminoethyl)phenyl](chloro){dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]-lambda5-phosphanylidene}palladium,2′-(dicyclohexylphosphanyl)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine-(2′-aminobiphenyl-2-yl)(chloro)palladium,chloro(2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II),[2′-(azanidyl-kappaN)biphenyl-2-yl-kappaC2](chloro){dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]-lambda5-phosphanyl}palladium,(2′-aminobi-phenyl-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,(2′-aminobiphenyl-2-yl)palladium(1+)methanesulfonate-di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane-[2-(2-aminoethyl)phenyl](chloro)palladium, (2′-aminobiphenyl-2-yl)palladium(1+)methanesulfonate-2′-(dicyclohexylphosphanyl)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine,sodium2′-(dicyclohexylphosphanyl)-2,6-dimethoxybiphenyl-3-sulfonate-(2′-aminobiphenyl-2-yl)(chloro)palladium,chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II),(2′-aminobiphenyl-2-yl)(methane-sulfonato-kappaO)palladium-[2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl) phosphane,(2′-aminobiphenyl-2-yl)(methanesulfonato-kappaO)palladium-dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,(2′-aminobiphenyl-2-yl)palladium(1+)methanesulfonate-dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane-(2′-aminobiphenyl-2-yl)(chloro)palladium,(2′-aminobiphenyl-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane,(2′-aminobiphenyl-2-yl)(methanesulfonato-kappaO)palladium-dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphaneor the following ligands:

racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, rac-BINAP,1,1′-bis(diphenyl-phosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethylphosphoniumtetrafluoroborate, 2-(di-tert-butylphosphino)biphenyl,tri-tert-butylphosphonium tetrafluoroborate, tri-2-furylphosphine,tris(2,4-di-tert-butylphenyl)phosphite, tri-o-tolylphosphine,(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine,di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine,di-tert-butyl(2′,4′,6′-triiso propylbiphenyl-2-yl)phosphine,dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine,di-tert-butyl(2′,4′,6′-triisopropyl-3-methoxy-6-methylbiphenyl-2-yl)phos-phine,di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine,adamantan-1-yl(adamantan-2-yl)(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine,dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine,dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine,2′-(dicyclohexylphosphino)-N,N-dimethyl-biphenyl-2-amine,2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine,2′-(di-phenylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine,di-tert-butyl(2′,4′,6′-tricyclohexyl-3,6-dimethoxybiphenyl-2-yl)phosphine,bis[3,5-bis(trifluoromethyl)phe-nyl](2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine,biphenyl-2-yl(di-tert-butyl)phosphine,dicyclohexyl(2′-methylbiphenyl-2-yl)phosphine, biphenyl-2-yl(dicyclohexyl)phosphine,2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine,2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine,sodium 2′-(dicyclohexylphosphino)-2,6-diisopropylbiphenyl-4-sulfonate,sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate,1,1′-binaphthalen-2-yl(di-tert-butyl)phosphine,1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene,1,3-bis[2,6-di(propan-2-yl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene.

Scheme 3:

Route for the preparation of compounds of general formula (I) in whichR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I),supra.

Compounds of general formulae (XVI), (IV), (VI) and (X) are eithercommercially available or can be prepared according to proceduresavailable from the public domain, as understandable to the personskilled in the art. Specific examples are described in the ExperimentalSection.

Nitriles of general formula (XVII) can be prepared from nitriles ofgeneral formula (XVI) and triazolinones of general formula (IV) in thepresence of a base. In connection with the method of the invention, theuse of potassium carbonate as base in acetonitrile at 80° C. waspreferable.

The formation of benzoates of general formula (XVIII) can beaccomplished by hydrolysis of nitriles of general formula XVII usingstrong acids or bases. In connection with the method of the invention,the use of sodium hydroxide in ethanol at 85° C. was preferable.

The compounds of general formula (XIX) can be prepared by the reactionof the benzoic acids of general formula (XVIII) with amines of generalformula (X) by amide coupling.

Suitable coupling reagents for the reaction of benzoic acids of generalformula (XVIII) with amines of general formula (X) are for exampleO-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide or a combination of1H-benzotria-1-ol and 1-ethyl-3-[3-(diemthylaminopropyl]carbodiimidehydrochloride.

Suitable organic bases for the amide coupling of benzoic acids ofgeneral formula (XVIII) with amines of general formula (X) are forexample 4-(dimethylamino)pyridine, N-ethyl-N,N-diisopropylamine,N-methylpyrollidine, or triethylamine.

Suitable solvents for the for the amide coupling of benzoic acids ofgeneral formula (XVIII) with amines of general formula (X) are forexample N,N-dimethylformamide, dichoromethane or tetrahydrofuran.

For coupling of the amide bond, other methods which are well known tothe person skilled in the art are also suitable, such as a condensationbetween amine and acid using propanephosphonic acid anhydride (T3P) ascoupling reagent, or transformation of benzoic acids of general formula(XVIII) into their respective acid chlorides and subsequent reactionwith amines of general formula (X) as described above.

In connection with the invention, formation of the compounds of generalformula (XIX) were preferrably accomplished by HATU mediated amidecoupling of benzoic acids of general formula (XVIII) and amines ofgeneral formula (X).

The formation of compounds of general formula (I) can be accomplished byreaction of amides of general formula (XIX) and alcohols of generalformula (VI) in the presence of a base. Bases that can be employed forthe reaction of amides of general formula (XIX) with alcohols of generalformula (VI) are for example sodium hydride, sodium tert-butanolate,potassium tert-butanolate, or cesium carbonate. In connection with themethod of the invention, sodium hydride was preferrably used as organicbase.

Solvents that can be used for the reactions of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are forexample tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide.In connection with the method according to the inventionN,N-dimethylformamide was preferrably used as solvent.

Reaction temperatures for the reactions of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are forexample ranging from room temperature to 80° C. In connection with themethod of the invention, the reaction of alcohols of general formula(VI) with sodium hydride was preferably performed at room temperaturefor 1 h before addition of amides of formula (XIX) and subsequentheating of the reaction mixture to 80° C.

Suitable reaction times for the reaction of tert-butyl benzoates ofgeneral formula (V) with alcohols of general formula (VI) are rangingfrom 3 h to several days.

Scheme 4:

Route for the preparation of compounds of general formula (I) in whichR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I),supra.

Compounds of general formulae (II), (IV), (VI) and (X) are eithercommercially available or can be prepared according to proceduresavailable from the public domain, as understandable to the personskilled in the art. Specific examples are described in the ExperimentalSection.

Amides of general formula (XX) can be prepared by the reaction of thebenzoic acids of general formula (II) with amines of general formula (X)by amide coupling.

Suitable coupling reagents for the reaction of benzoic acids of generalformula (II) with amines of general formula (X) are for exampleO-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide or a combination of1H-benzotria-1-ol and 1-ethyl-3-[3-(diemthylaminopropyl]carbodiimidehydrochloride.

Suitable organic bases for the amide coupling of benzoic acids ofgeneral formula (II) with amines of general formula (X) are for example4-(dimethylamino)pyridine, N-ethyl-N,N-diisopropylamine,N-methylpyrollidine, or triethylamine.

Suitable solvents for the for the amide coupling of benzoic acids ofgeneral formula (II) with amines of general formula (X) are for exampleN,N-dimethylformamide, dichoromethane or tetrahydrofuran.

For coupling of the amide bond, other methods which are well known tothe person skilled in the art are also suitable, such as a condensationbetween amine and acid using propanephosphonic acid anhydride (T3P) ascoupling reagent, or transformation of benzoic acids of general formula(II) into their respective acid chlorides and subsequent reaction withamines of general formula (X) as described above.

In connection with the invention, formation of the compounds of generalformula (XX) were preferrably accomplished by HATU mediated amidecoupling of benzoic acids of general formula (II) and amines of generalformula (X).

Alternatively, amides of general formula (XX) can be prepared frombenzoic acid derivatives of general formula (II) by in situ formation ofthe corresponding acid chlorides and subsequent reaction with amines ofgeneral formula (X).

In situ formation of acid chlorides from benzoic acids of generalformular (II) can be accomplished, for example by using oxalyl chlorideor thionyl chloride, both reagents used in the presence of catalyticamount of N,N-dimethylformamide.(XX)+(IV)→(XIX):

The formation of compounds of general formula (XIX) can be accomplishedby the reaction of triazolinones of general formula (IV) with amides ofgeneral formula (XX) in the presence of a base, such as potassiumcarbonate. In connection with the method of the invention, the use of1,8-diazabicyclo[5.4.0]undec-7-ene as organic base in acetonitrile at80° C. was preferable.

The formation of compounds of general formula (I) can be accomplished byreaction of amides of general formula (XIX) and alcohols of generalformula (VI) in the presence of a base. Bases that can be employed forthe reaction of amides of general formula (XIX) with alcohols of generalformula (VI) are for example sodium hydride, sodium tert-butanolate,potassium tert-butanolate, or cesium carbonate. In connection with themethod of the invention, sodium hydride was preferrably used as organicbase.

Solvents that can be used for the reactions of amides of general formula(XIX) with alcohols of general formula (VI) are for exampletetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide. Inconnection with the method according to the inventionN,N-dimethylformamide was preferrably used as solvent.

Reaction temperatures for the reactions of amides of general formula(XIX) with alcohols of general formula (VI) are for example ranging fromroom temperature to 140° C. In connection with the method of theinvention, the reaction of alcohols of general formula (VI) with sodiumhydride was preferably performed at room temperature for 1 h beforeaddition of amides of formula (XIX) and subsequent heating of thereaction mixture to 80° C.

Suitable reaction times for the reaction of amides of general formula(XIX) with alcohols of general formula (VI) are ranging from 3 h toseveral days.

Scheme 5:

Alternative route for the preparation of compounds of general formula(VIII) in which R², R³, R⁴ and R⁵ have the meaning as given for generalformula (I), supra, and A represents a chlorine, bromine or iodine atom.

An alternative synthesis of compounds of formula (VIII) is described inscheme 5.

Compounds of general formula (XXI) can be prepared from halides ofgeneral formula (XII) and from triazolones of general formula (IV) usingtransition metals as catalysts.

The formation of benzoates of general formula (VIII) can be accomplishedby hydrolysis of nitriles of general formula XXI using strong acids orbases. In connection with the method of the invention, the use ofsulphuric acid, acetic acid and water at 120° C. was preferable.

The synthesis of compounds of general formula (XII) and the synthesis ofcompounds of general formula (I) from compounds of general formula(VIII) is described above.

The order of transformations exemplified in these schemes is thereforenot intended to be limiting. In addition, interconversion of any of thesubstituents, R¹, R², R³, R⁴ or R⁵ can be achieved before and/or afterthe exemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3^(rd) edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

The resulting compounds of general formula (I) are optionally convertedwith corresponding (i) solvents and/or (ii) bases or acids to theirsolvates, salts and/or solvates of the salts, in which R¹, R², R³, R⁴and R⁵ have the meaning as given for general formula (I), supra.

In accordance with another aspect, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (VIII):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (X):

in which R¹ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R are as defined supra.

In accordance with certain embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (IX):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (X):

in which R¹ is as defined for the compound of general formula (i) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra.

In accordance with further embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XV):

in which R¹, R² and R³ are as defined for the compound of generalformula (I) as defined supra, and A represents a chlorine, bromine oriodine atom,to react with a compound of general formula (IV):

in which R⁴ and R⁵ are as defined for the compound of general formula(I) as defined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra.

In accordance with other embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XVIII):

in which R², R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (X):

in which R¹ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined supra.

In accordance with other embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XX):

in which R¹ and R² are as defined for the compound of general formula(I) as defined supra,to react with a compound of general formula (IV):

in which R⁴ and R⁵ are as defined for the compound of general formula(I) as defined supra,thereby giving a compound of general formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra.

In accordance with further embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (VI):

in which R³ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra.

In accordance with another aspect, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,

said methods comprise the step of allowing an intermediate compound ofgeneral formula (VIII):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (X):

in which R¹ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra,then optionally converting said compound into solvates, salts and/orsolvates of such salts using the corresponding (i) solvents and/or (ii)bases or acids.

In accordance with certain embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (IX):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (X):

in which R¹ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra,then optionally converting said compound into solvates, salts and/orsolvates of such salts using the corresponding (i) solvents and/or (ii)bases or acids.

In accordance with further embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XV):

in which R¹, R² and R³ are as defined for the compound of generalformula (I) as defined supra, and A represents a chlorine, bromine oriodine atom,to react with a compound of general formula (IV):

in which R⁴ and R⁵ are as defined for the compound of general formula(I) as defined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra,then optionally converting said compound into solvates, salts and/orsolvates of such salts using the corresponding (i) solvents and/or (ii)bases or acids.

In accordance with other embodiments, the present invention providesmethods of preparing compounds of general formula (I) as defined supra,said methods comprising the step of allowing an intermediate compound ofgeneral formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined for the compound of generalformula (I) as defined supra,to react with a compound of general formula (VI):

in which R³ is as defined for the compound of general formula (I) asdefined supra,thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴ and R⁵ are as defined supra,then optionally converting said compound into solvates, salts and/orsolvates of such salts using the corresponding (i) solvents and/or (ii)bases or acids.

The present invention provides methods of preparing compounds of thepresent invention of general formula (I), said methods comprising thesteps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention providesintermediate compounds which are useful for the preparation of thecompounds of general formula (I), supra.

Particularly, the invention provides the intermediate compounds ofgeneral formula (IV):

in which R⁴ and R⁵ are as defined for the compound of general formula(I) supra.

Particularly, the invention provides the intermediate compounds ofgeneral formula (VI):

in which R³ is as defined for the compound of general formula (I) supra.

Particularly, the invention provides the intermediate compounds ofgeneral formula (VIII):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra.

Particularly, the inventions provides the intermediate compounds ofgeneral formula (IX):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra.

Particularly, the inventions provides the intermediate compounds ofgeneral formula (XV):

in which R¹, R² and R³ are as defined for the compound of generalformula (I) supra, and A represents a chlorine, bromine or iodine atom.

Particularly, the inventions provides the intermediate compounds ofgeneral formula (XVIII):

in which R², R⁴ and R⁵ are as defined for the compound of generalformula (I) supra.

Particularly, the invention provides the intermediate compounds ofgeneral formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined for the compound of generalformula (I) supra.

Particularly, the invention provides the intermediate compounds ofgeneral formula (XXI):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra.

In accordance with another aspect, the present invention provides theuse of said intermediate compounds for the preparation of a compound ofgeneral formula (I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (IV):

in which R⁴ and R⁵ are as defined for the compound of general formula(I) supra, for the preparation of a compound of general formula (I) asdefined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (VI):

in which R³ is as defined for the compound of general formula (I) supra,for the preparation of a compound of general formula (I) as definedsupra.

Particularly, the invention provides the use of intermediate compoundsof general formula (VIII):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra, for the preparation of a compound of general formula(I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (IX):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra, for the preparation of a compound of general formula(I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (X):

in which R¹ is as defined for the compound of general formula (I) asdefined supra, for the preparation of a compound of general formula (I)as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (XV):

in which R¹, R² and R³ are as defined for the compound of generalformula (I) supra, and A represents a chlorine, bromine or iodine atom,for the preparation of a compound of general formula (I) as definedsupra.

Particularly, the invention provides the use of intermediate compoundsof general formula (XVIII):

in which R², R⁴ and R⁵ are as defined for the compound of generalformula (I) supra, for the preparation of a compound of general formula(I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (XIX):

in which R¹, R², R⁴ and R⁵ are as defined for the compound of generalformula (I) supra, for the preparation of a compound of general formula(I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (XX):

in which R¹ and R² are as defined for the compound of general formula(I) as defined supra, for the preparation of a compound of generalformula (I) as defined supra.

Particularly, the invention provides the use of intermediate compoundsof general formula (XXI):

in which R², R³, R⁴ and R⁵ are as defined for the compound of generalformula (I) supra, for the preparation of a compound of general formula(I) as defined supra.

The present invention provides the use of the intermediate compounds ofgeneral formula (IV), (VI), (VIII), (IX), (X), (XV), (XVIII), (XIX) and(XXI) which are disclosed in the Example Section of this text, infra.

The present invention provides the intermediate compounds which aredisclosed in the Example Section of this text, infra.

The present invention provides the intermediate compounds of generalformula (IV), (VI), (VIII), (IX), (X), (XV), (XVIII), (XIX) and (XXI)which are disclosed in the Example Section of this text, infra.

The present invention provides any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformula (IV), (VI), (VIII), (IX), (X), (XV), (XVIII), (XIX) and (XXI),supra.

The compounds of general formula (I) of the present invention can beconverted to any salt, preferably pharmaceutically acceptable salts, asdescribed herein, by any method which is known to the person skilled inthe art. Similarly, any salt of a compound of general formula (I) of thepresent invention can be converted into the free compound, by any methodwhich is known to the person skilled in the art.

Compounds of general formula (I) of the present invention demonstrate avaluable pharmacological spectrum of action, which could not have beenpredicted. Compounds of the present invention have surprisingly beenfound to effectively inhibit DHODH and it is possible therefore thatsaid compounds be used for the treatment or prophylaxis of diseases,preferably hyperproliferative and/or inflammatory disorders in humansand animals.

Compounds of the present invention can be utilized to inhibit theactivity of DHODH. This method comprises administering to a mammal inneed thereof, including a human, an effective amount of a compound ofgeneral formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of hyperproliferative and/or inflammatorydisorders.

Another aspect of the invention is a method of inhibiting proliferationof a cell, comprising contacting the cell with a compound of formula(I).

Hyperproliferative disorders include, but are not limited to, forexample: psoriasis, keloids, and other hyperplasias affecting the skin,benign prostate hyperplasia (BPH), solid tumours, such as cancers of thebreast, respiratory tract, brain, reproductive organs, digestive tract,urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid andtheir distant metastases. Those disorders also include sarcomas, andhaematological malignancies including but not limited to leukemias,lymphomas, multiple myeolomas.

One aspect of the invention is the use of the compounds of formula (I)for the treatment of cancer, the compounds of formula (I) for use in thetreatment of cancer as well as a method of treatment of cancer diseasescomprising administering a specific amount of a compound of formula (I).

Examples of breast cancers include, but are not limited to, invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to, small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brain stemand hypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited to,prostate and testicular cancer.

Tumours of the female reproductive organs include, but are not limitedto, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as wellas sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to, anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to, bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to, intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to,hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to, laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell.

Lymphomas include, but are not limited to, AIDS-related lymphoma,chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma (NHL),T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse LargeCell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-celllymphoma DLBCL, double-hit lymphoma and double-expressor lymphoma;anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-celllymphoma, Burkitt's lymphoma, follicular lymphoma, hairy cell lymphoma,Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma of the centralnervous system, small lymphocytic lymphoma and chronic lymphocyticlymphoma and Sezary syndrome.

Sarcomas include, but are not limited to, sarcoma of the soft tissue,gliosarcoma, osteosarcoma, malignant fibrous histiocytoma,lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to acute lymphoblastic leukemia,acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblasticleukemia, acute lymphocytic leukemia (ALL), acute monocytic leukemia(AML), acute promyelocytic leukemia (APL), bisphenotypic Bmyelomonocytic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, chronic myeloid leukemia (CML), chronicmyelomonocytic leukemia (CMML), large granular lymphocytic leukemia,plasma cell leukemia, and also myelodysplastic syndrome (MDS), which candevelop into an acute myeloid leukemia.

Inhibition of DHODH can also lead to differentiation of tumor initiatingcells in hematological and solid cancers, especially leukemias.

The present invention also provides methods of treating angiogenicdisorders including diseases associated with excessive and/or abnormalangiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, for example,diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathyof prematurity [Aiello et al., New Engl. J. Med., 1994, 331, 1480, Peeret al., Lab. Invest., 1995, 72, 638], age-related macular degeneration(AMD) [Lopez et al., Invest. Opththalmol. Vis. Sci., 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of general formula (I) of thepresent invention can be utilized to treat and/or prevent any of theaforementioned angiogenesis disorders, for example by inhibiting and/orreducing blood vessel formation; by inhibiting, blocking, reducing,decreasing, etc. endothelial cell proliferation, or other types involvedin angiogenesis, as well as causing cell death or apoptosis of such celltypes.

Another aspect of the invention is a method for controlling cancer(e.g., through treatment, prophylaxis, etc.) in a subject (e.g., human,rat, etc.) by administering an effective amount of at least one compoundof general formula (I), or a pharmaceutically acceptable salt,polymorph, metabolite, hydrate, solvate or ester thereof to the subject.

In some embodiments, the subject may be administered a medicament,comprising at least one compound of general formula (I) of the presentinvention and one or more pharmaceutically acceptable carriers,excipients and/or diluents.

In some embodiments, the method of treatment and/or prophylaxis of ahyperproliferative disorder in a subject may comprise administering tothe subject an effective amount of a compound of general formula (I).The hyperproliferative disorder may be, for example, cancer (the cancertypes as defined supra, more particularly leukemia, lymphoma, solidtumors, such as e.g. colorectal carcinoma, lung cancer, ovarian cancer,pancreatic cancer, renal cancer, even more particularly e.g. acutemyeloid leukemia, colorectal carcinoma, leukemia, lung cancer, lymphoma,multiple myeloma, ovarian cancer, pancreatic cancer and renal cellcarcinoma).

In some embodiments, the method of treatment and/or prophylaxis of ahyperproliferative disorder in a subject may comprise administering tothe subject an effective amount of a compound of general formula (I).The hyperproliferative disorder may be, for example, cancer (e.g., lungcancer, acute myeloid leukemia, acute promyelocytic leukemia (APL),mixed-lineage leukemia (MLL), chronic myeloid leukemia (CML),myelodysplastic syndrome (MDS), lymphoma, glioblastoma, prostate cancer,or any other cancer indication as defined herein).

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the preparation of a medicament for the treatment orprophylaxis of a disease.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer, which cancer is selected fromacute myeloid leukemia, colorectal carcinoma, leukemia, lung cancer,lymphoma, multiple myeloma, ovarian cancer, pancreatic cancer and renalcell carcinoma.

In another aspect the invention provides methods of treatment of cancercomprising administering a compound of general formula (I) or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, where the cancer is selected from acutemyeloid leukemia, colorectal carcinoma, leukemia, lung cancer, lymphoma,multiple myeloma, ovarian cancer, pancreatic cancer and renal cellcarcinoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer, which cancer is selected fromacute myeloid leukemia, breast cancer, colorectal carcinoma, gastriccancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma,leukemia, lung cancer, lymphoma, multiple myeloma, neuroblastoma,ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, and sarcoma.

In another aspect the invention provides methods for the treatment ofcancer comprising administering a compound of general formula (I) or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, where the cancer is selected from acutemyeloid leukemia, breast cancer, colorectal carcinoma, gastric cancer,gliosarcoma, head & neck cancer, hepatocellular carcinoma, leukemia,lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreaticcancer, prostate cancer, renal cell carcinoma, and sarcoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer, which cancer is selected fromacute T-cell lymphoblastic leukemia, acute promyelocytic leukemia, acutemyeloid leukemia, anaplastic large cell lymphoma, biphenotypic Bmyelomonocytic leukemia, B-cell lymphoma, breast cancer, Burkittlymphoma, chronic myeloid leukemia, colorectal carcinoma, gastriccancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lungcancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreaticcancer, prostate cancer, renal cell carcinoma, sarcoma and T-celllymphoma. In another aspect the invention provides methods of treatmentof cancer comprising administering a compound of general formula (I) ora pharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, where the cancer is selected from acute T-celllymphoblastic leukemia, acute promyelocytic leukemia, acute myeloidleukemia, anaplastic large cell lymphoma, biphenotypic B myelomonocyticleukemia, B-cell lymphoma, breast cancer, Burkitt lymphoma, chronicmyeloid leukemia, colorectal carcinoma, gastric cancer, gliosarcoma,head & neck cancer, hepatocellular carcinoma, lung cancer, multiplemyeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostatecancer, renal cell carcinoma, sarcoma and T-cell lymphoma.

In another aspect, the present invention provides methods of treatingcancer, which cancer is selected from lung cancer, leukemia, acutemyeloid leukemia, gliosarcoma, colorectal carcinoma, head & neck cancer,hepatocellular carcinoma, multiple myeloma, lymphoma, breast cancer,neuroblastoma, ovarian cancer, gastric cancer, pancreatic cancer,prostate cancer, renal cell carcinoma, and sarcoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer, which cancer is selected from lungcancer, leukemia, acute myeloid leukemia, gliosarcoma, colorectalcarcinoma, head & neck cancer, hepatocellular carcinoma, multiplemyeloma, lymphoma, breast cancer, neuroblastoma, ovarian cancer, gastriccancer, pancreatic cancer, prostate cancer, renal cell carcinoma, andsarcoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer, which cancer is selected fromleukemias, lymphomas, sarcomas and solid tumors.

In another aspect the invention provides methods for the treatment ofcancer comprising administering a compound of general formula (I) or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, wherein the cancer is selected from leukemias,lymphomas, sarcomas and solid tumors.

In another aspect, the present invention provides methods for use of acompound of general formula (I) of the present invention, or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, for the treatment of cancer and methods oftreating cancer, which cancer is selected from colorectal cancer,leukemia and lymphoma. In another aspect the invention provides methodsfor the treatment of cancer comprising administering a compound ofgeneral formula (I) or a pharmaceutically acceptable salt, polymorph,metabolite, hydrate, solvate or ester thereof, wherein the cancer isselected from colorectal cancer, leukemia and lymphoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of cancer and methods of treating cancer,which cancer is selected from colorectal cancer, leukemia and lymphoma.In another aspect the invention provides methods of treatment of cancercomprising administering a compound of general formula (I) or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, wherein the cancer is selected from colorectalcancer, leukemia and lymphoma.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of one or more cancer types and methods oftreating one or more cancer types, where cancer is selected from ALL,AML, APL, CMML, DLBCL, MDS, MCL, T-NHL, colorectal cancer, melanoma andovarian cancer.

In another aspect the invention provides methods for the treatment ofcancer comprising administering a compound of general formula (I) or apharmaceutically acceptable salt, polymorph, metabolite, hydrate,solvate or ester thereof, where the cancer is selected from ALL, AML,APL, CMML, DLBCL, MDS, MCL, T-NHL, colorectal cancer, melanoma andovarian cancer.

In another aspect, the present invention provides the use of a compoundof general formula (I) of the present invention, or a pharmaceuticallyacceptable salt, polymorph, metabolite, hydrate, solvate or esterthereof, for the treatment of one or more cancer types, where cancer isselected from

-   leukemias including but not limited to acute lymphoblastic leukemia    (ALL), acute myeloid leukemia (AML), acute T-cell leukemia, acute    monocytic leukemia, acute promyelocytic leukemia (APL),    bisphenotypic B myelomonocytic leukemia, chronic myelogenous    leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia    (CMML), large granular lymphocytic leukemia, and myelodysplastic    syndrome (MDS), which can develop into an acute myeloid leukemia,-   lymphomas including but not limited to AIDS-related lymphoma,    chronic lymphocytic lymphoma, non-Hodgkin's lymphoma (NHL),    T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse    Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center    B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma;    anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell    lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell    lymphoma, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma of    the central nervous system, small lymphocytic lymphoma and chronic    lymphocytic lymphoma;-   sarcomas including but not limited to sarcoma of the soft tissue,    gliosarcoma, osteosarcoma, malignant fibrous histiocytoma,    lymphosarcoma, and rhabdomyosarcoma;    and-   solid tumors including but not limited to breast cancer, colorectal    carcinoma, gastric cancer, gliosarcoma, head & neck cancer,    hepatocellular carcinoma, lung cancer, multiple myeloma,    neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer,    renal cell carcinoma and sarcoma.

In another aspect the invention provides method for the treatment ofcancer comprising administering an effective amount of a compound ofgeneral formula (I) where the cancer is selected from

-   leukemias including but not limited to acute lymphoblastic leukemia    (ALL), acute myeloid leukemia (AML), acute T-cell leukemia, acute    monocytic leukemia, acute promyelocytic leukemia, bisphenotypic B    myelomonocytic leukemia, chronic myelogenous leukemia, chronic    myeloid leukemia, chronic myelomonocytic leukemia (CMML), large    granular lymphocytic leukemia, and myelodysplastic syndrome (MDS),    which can develop into an acute myeloid leukemia,-   lymphomas including but not limited to AIDS-related lymphoma,    chronic lymphocytic lymphoma, non-Hodgkin's lymphoma (NHL),    T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse    Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center    B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma;    anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell    lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell    lymphoma, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma of    the central nervous system, small lymphocytic lymphoma and chronic    lymphocytic lymphoma;-   sarcomas including but not limited to sarcoma of the soft tissue,    gliosarcoma, osteosarcoma, malignant fibrous histiocytoma,    lymphosarcoma, and rhabdomyosarcoma;    and-   solid tumors including but not limited to breast cancer, colorectal    carcinoma, gastric cancer, gliosarcoma, head & neck cancer,    hepatocellular carcinoma, lung cancer, multiple myeloma,    neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer,    renal cell carcinoma and sarcoma.

In another aspect, the present invention provides a method forinhibiting cell proliferation or viability in a cancer cell, the methodcomprising contacting the cell with any compound of any claim, aspect orembodiment disclosed herein, thereby inhibiting cell proliferation orviability.

In a further aspect the present invention provides a method forinhibiting Dihydroorotate Dehydrogenase (DHODH) enzymatic activity, themethod comprising contacting DHODH with any compound of any claim,aspect or embodiment disclosed herein, thereby inhibiting DHODHenzymatic activity.

In yet a further aspect the present invention provides a method fortreating lymphoma in a subject, the method comprising administering tothe subject an effective amount of any compound of any claim, aspect orembodiment disclosed herein, thereby treating the lymphoma.

In yet a further aspect the present invention provides a method fortreating lymphoma mentioned above in a subject, wherein the lymphoma isselected from the group AIDS-related lymphoma, chronic lymphocyticlymphoma (CLL), non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma(T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL),activated B-cell DLBCL, germinal center B-cell DLBCL, double-hitlymphoma and double-expressor lymphoma; anaplastic large cell lymphoma,B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, follicularlymphoma, hairy cell lymphoma, Hodgkin's disease, mantle cell lymphoma(MCL), lymphoma of the central nervous system, small lymphocyticlymphoma and chronic lymphocytic lymphoma.

In another aspect, the present invention provides a method for treatingleukemia in a subject, the method comprising administering to thesubject an effective amount of any compound of any claim, aspect orembodiment disclosed herein, thereby treating the leukemia.

In yet a further aspect the present invention provides a method fortreating leukemia mentioned above, wherein the leukemia is selected fromthe group acute lymphoblastic leukemia, acute myeloid leukemia, (acute)T-cell leukemia, acute lymphoblastic leukemia, acute lymphocyticleukemia, acute monocytic leukemia, acute promyelocytic leukemia,bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, chronic myeloid leukemia, chronicmyelomonocytic leukemia, large granular lymphocytic leukemia, plasmacell leukemia, and also myelodysplastic syndrome, which can develop intoan acute myeloid leukemia.

In another aspect, the present invention provides methods for treatingor preventing a disease or condition associated with inflammation, ametabolic disorder, infection or an immune disease or condition byadministering to a subject having such condition or disease, atherapeutically effective amount of a compound or composition of theinvention.

In further embodiments, diseases or conditions, including chronicdiseases, of humans or other species can be treated or prevented byinhibition of DHODH. These diseases or conditions include (1)inflammatory or allergic diseases such as systemic anaphylaxis andhypersensitivity responses, drug allergies, insect sting allergies andfood allergies, (2) inflammatory bowel diseases, such as Crohn'sdisease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4)psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopicdermatitis, allergic contact dermatitis and urticaria, (5) vasculitis,(6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratoryallergic diseases such as allergic asthma, allergic rhinitis, allergicconjunctivitis, hypersensitivity lung diseases and the like, and (9)autoimmune diseases, such as arthritis (including rheumatoid andpsoriatic), systemic lupus erythematosus, type I diabetes,glomerulonephritis and the like, (10) graft rejection (includingallograft rejection and graft-v-host disease), (11) other diseases inwhich undesired inflammatory responses are to be inhibited, e.g.,atherosclerosis, myositis, neurological disorders such as stroke,ischemic reperfusion injury, traumatic brain injury and closed-headinjuries, neurodegenerative diseases (e.g., Parkinson's disease),multiple sclerosis, Alzheimer's disease, encephalitis, meningitis,osteoporosis, gout, hepatitis, nephritis, gall bladder disease, sepsis,sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonarydisease, sinusitis and Behcet's syndrome, and (12) immune diseases orconditions.

In another aspect, the present invention provides methods for treatingor preventing viral infections in a subject, the methods comprisingadministering to a subject having or at risk of developing a viralinfection a therapeutically effective amount of a compound of theinvention.

In yet another aspect, the present invention provides methods oftreating or preventing Malaria, the method comprising administering to asubject having or at risk of developing Malaria a therapeuticallyeffective amount of a compound of the invention.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

If it is stated “preventing or treating” or “treatment or prophylaxis”or the like, treating/treatment is preferred.

The term “treating” or “treatment” as stated throughout this document isused conventionally, for example the management or care of a subject forthe purpose of combating, alleviating, reducing, relieving, improvingthe condition of a disease or disorder, such as a carcinoma.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Generally, the use of chemotherapeutic agents and/or anti-cancer agentsin combination with a compound or pharmaceutical composition of thepresent invention will serve to:

-   -   1. yield better efficacy in reducing the growth of a tumour or        even eliminate the tumour as compared to administration of        either agent alone,    -   2. provide for the administration of lesser amounts of the        administered chemotherapeutic agents,    -   3. provide for a chemotherapeutic treatment that is well        tolerated in the patient with fewer deleterious pharmacological        complications than observed with single agent chemotherapies and        certain other combined therapies,    -   4. provide for treating a broader spectrum of different cancer        types in mammals, especially humans,    -   5. provide for a higher response rate among treated patients,    -   6. provide for a longer survival time among treated patients        compared to standard chemotherapy treatments,    -   7. provide a longer time for tumour progression, and/or    -   8. yield efficacy and tolerability results at least as good as        those of the agents used alone, compared to known instances        where other cancer agent combinations produce antagonistic        effects.

In addition, the compounds of general formula (I) of the presentinvention can also be used in combination with radiotherapy and/orsurgical intervention.

In a further embodiment of the present invention, the compounds ofgeneral formula (I) of the present invention may be used to sensitize acell to radiation, i.e. treatment of a cell with a compound of thepresent invention prior to radiation treatment of the cell renders thecell more susceptible to DNA damage and cell death than the cell wouldbe in the absence of any treatment with a compound of the presentinvention. In one aspect, the cell is treated with at least one compoundof general formula (I) of the present invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the presentinvention in combination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of general formula (I) of the present invention prior to thetreatment of the cell to cause or induce cell death. In one aspect,after the cell is treated with one or more compounds of general formula(I) of the present invention, the cell is treated with at least onecompound, or at least one method, or a combination thereof, in order tocause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In other embodiments the invention relates to a method for the treatmentof cancer comprising contacting a cell with at least one DNA damagingagent and a compound of the invention, thereby treating the cancer. Inone embodiment, the DNA damaging agent contacts the cell prior to,during, or concurrently with a compound of the invention. In anotherembodiment, contacting the cell with one or more compounds of generalformula (I) of the present invention sensitizes the cell to cell death.

In other embodiments of the present invention, a cell is killed bytreating the cell with at least one DNA damaging agent, i.e. aftertreating a cell with one or more compounds of general formula (I) of thepresent invention to sensitize the cell to cell death, the cell istreated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g. cis platin), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In other embodiments, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of general formula (I) of thepresent invention is administered to a cell prior to the radiation orother induction of DNA damage in the cell.

Thus in other embodiments of the invention the invention relates to amethod for the treatment of cancer in a subject comprising administeringto the subject an effective amount of a compound of formula (I) priorto, during, or concurrently with exposing the subject to radiationand/or administration of a DNA damaging agent.

In another aspect of the invention, a compound of general formula (I) ofthe present invention is administered to a cell concomitantly with theradiation or other induction of DNA damage in the cell.

In yet another aspect of the invention, a compound of general formula(I) of the present invention is administered to a cell immediately afterradiation or other induction of DNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

In accordance with a further aspect, the present invention providescompounds of general formula (I), as described supra, or tautomers,N-oxides, and salts thereof, or salts of tautomers or N-oxides,particularly pharmaceutically acceptable salts thereof, or mixtures ofsame, for use in the treatment or prophylaxis of diseases, in particularhyperproliferative and/or inflammatory disorders.

In accordance with a further aspect, the present invention providescompounds of general formula (I), as described supra, or tautomers,N-oxides, and salts thereof, or salts of tautomers or N-oxides,particularly pharmaceutically acceptable salts thereof, or mixtures ofsame, for use in the treatment or prophylaxis of diseases, in particularinflammatory disorders.

In accordance with a further aspect, the present invention providescompounds of general formula (I), as described supra, or tautomers,N-oxides, and salts thereof, or salts of tautomers or N-oxides, for usein the treatment or prophylaxis of diseases, in particularhyperproliferative disorders, particularly benign hyperproliferativedisorders, more particularly cancer.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their activity as DHODH inhibitors.

In accordance with a further aspect, the present invention provides theuse of compounds of general formula (I), as described supra, ortautomers, N-oxides, and salts thereof, or salts of tautomers orN-oxides, particularly pharmaceutically acceptable salts thereof, ormixtures of same, for the treatment or prophylaxis of diseases, inparticular hyperproliferative and/or inflammatory disorders.

In accordance with a further aspect, the present invention provides theuse of compounds of general formula (I), as described supra, ortautomers, N-oxides, and salts thereof, or salts of tautomers orN-oxides, particularly pharmaceutically acceptable salts thereof, ormixtures of same, for the treatment or prophylaxis of diseases, inparticular hyperproliferative disorders, particularly benignhyperproliferative disorders, more particularly cancer.

In accordance with a further aspect, the present invention provides theuse of compounds of general formula (I), as described supra, ortautomers, N-oxides, and salts thereof, or salts of tautomers orN-oxides, particularly pharmaceutically acceptable salts thereof, ormixtures of same, in a method of treatment or prophylaxis of diseases,in particular hyperproliferative and/or inflammatory disorders,particularly cancer.

In accordance with a further aspect, the present invention provides theuse of compounds of general formula (I), as described supra, ortautomers, N-oxides, and salts thereof, or salts of tautomers orN-oxides, particularly pharmaceutically acceptable salts thereof, ormixtures of same, in a method of treatment or prophylaxis of diseases,in particular hyperproliferative disorders, particularly benignhyperproliferative disorders, more particularly cancer.

In accordance with a further aspect, the present invention provides theuse of a compound of general formula (I), as described supra, or atautomer, an N-oxide, and a salt thereof, or a salt of a tautomer or anN-oxide, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the preparation of a medicament, for theprophylaxis or treatment of diseases, in particular hyperproliferativedisorders, particularly benign hyperproliferative disorders, moreparticularly cancer.

In accordance with a further aspect, the present invention provides useof a compound of general formula (I), as described supra, or a tautomer,an N-oxide, and a salt thereof, or a salt of a tautomer or an N-oxide,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the preparation of a pharmaceutical composition, for theprophylaxis or treatment of diseases, in particular hyperproliferativeand/or inflammatory disorders.

In accordance with a further aspect, the present invention provides useof a compound of general formula (I), as described supra, or a tautomer,an N-oxide, and a salt thereof, or a salt of a tautomer or an N-oxide,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the preparation of a pharmaceutical composition, preferably amedicament, for the prophylaxis or treatment of diseases, in particularhyperproliferative disorders, particularly benign hyperproliferativedisorders, more particularly cancer.

In accordance with a further aspect, the present invention provides amethod for the treatment or prophylaxis of diseases, in particularhyperproliferative and/or inflammatory disorders, comprisingadministering to a subject in need thereof an effective amount of acompound of general formula (I), as described supra, or a tautomer, anN-oxide, and a salt thereof, or a salt of a tautomer or an N-oxide,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame.

In accordance with a further aspect, the present invention provides amethod ofor the f treatment or prophylaxis of diseases, in particularhyperproliferative disorders, particularly benign hyperproliferativedisorders, more particularly cancer, comprising administering to asubject in need thereof an effective amount of a compound of generalformula (I), as described supra, or a tautomer, an N-oxide, and a saltthereof, or a salt of a tautomer or an N-oxide, particularly apharmaceutically acceptable salt thereof, or a mixture of same.

In accordance with a further aspect, the present invention providespharmaceutical compositions, in particular a medicament, comprising acompound of general formula (I), as described supra, or a tautomer, anN-oxide, and a salt thereof, or a salt of a tautomer or an N-oxide,particularly a pharmaceutically acceptable salt, or a mixture of same,and one or more excipients), in particular one or more pharmaceuticallyacceptable excipient(s). Conventional procedures for preparing suchpharmaceutical compositions in appropriate dosage forms can be utilized.

The present invention furthermore provides pharmaceutical compositions,in particular medicaments, which comprise at least one compoundaccording to the invention, conventionally together with one or morepharmaceutically suitable excipients, and to their use for the abovementioned purposes.

It is possible for the compounds according to the invention to havesystemic and/or local activity. For this purpose, they can beadministered in a suitable manner, such as, for example, via the oral,parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal,vaginal, dermal, transdermal, conjunctival, otic route or as an implantor stent.

For these administration routes, it is possible for the compoundsaccording to the invention to be administered in suitable administrationforms.

For oral administration, it is possible to formulate the compoundsaccording to the invention to dosage forms known in the art that deliverthe compounds of the invention rapidly and/or in a modified manner, suchas, for example, tablets (uncoated or coated tablets, for example withenteric or controlled release coatings that dissolve with a delay or areinsoluble), orally-disintegrating tablets, films/wafers,films/lyophylisates, capsules (for example hard or soft gelatinecapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions. It is possible to incorporate thecompounds according to the invention in crystalline and/or amorphisedand/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of anabsorption step (for example intravenous, intraarterial, intracardial,intraspinal or intralumbal) or with inclusion of absorption (for exampleintramuscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal). Administration forms which are suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophylisates orsterile powders.

Examples which are suitable for other administration routes arepharmaceutical forms for inhalation [inter alia powder inhalers,nebulizers], nasal drops, nasal solutions, nasal sprays;tablets/films/wafers/capsules for lingual, sublingual or buccaladministration; suppositories; eye drops, eye ointments, eye baths,ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, eartampons; vaginal capsules, aqueous suspensions (lotions, mixturaeagitandae), lipophilic suspensions, emulsions, ointments, creams,transdermal therapeutic systems (such as, for example, patches), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into thestated administration forms. This can be effected in a manner known perse by mixing with pharmaceutically suitable excipients. Pharmaceuticallysuitable excipients include, inter alia,

-   -   fillers and carriers (for example cellulose, microcrystalline        cellulose (such as, for example, Avicel®), lactose, mannitol,        starch, calcium phosphate (such as, for example, Di-Cafos®)),    -   ointment bases (for example petroleum jelly, paraffins,        triglycerides, waxes, wool wax, wool wax alcohols, lanolin,        hydrophilic ointment, polyethylene glycols),    -   bases for suppositories (for example polyethylene glycols, cacao        butter, hard fat),    -   solvents (for example water, ethanol, isopropanol, glycerol,        propylene glycol, medium chain-length triglycerides fatty oils,        liquid polyethylene glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetters (for example        sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols        (such as, for example, Lanette®), sorbitan fatty acid esters        (such as, for example, Span®), polyoxyethylene sorbitan fatty        acid esters (such as, for example, Tween®), polyoxyethylene        fatty acid glycerides (such as, for example, Cremophor®),        polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol        ethers, glycerol fatty acid esters, poloxamers (such as, for        example, Pluronic®),    -   buffers, acids and bases (for example phosphates, carbonates,        citric acid, acetic acid, hydrochloric acid, sodium hydroxide        solution, ammonium carbonate, trometamol, triethanolamine),    -   isotonicity agents (for example glucose, sodium chloride),    -   adsorbents (for example highly-disperse silicas),    -   viscosity-increasing agents, gel formers, thickeners and/or        binders (for example polyvinylpyrrolidone, methylcellulose,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        carboxymethylcellulose-sodium, starch, carbomers, polyacrylic        acids (such as, for example, Carbopol®); alginates, gelatine),    -   disintegrants (for example modified starch,        carboxymethylcellulose-sodium, sodium starch glycolate (such as,        for example, Explotab®), cross-linked polyvinylpyrrolidone,        croscarmellose-sodium (such as, for example, AcDiSol®)),    -   flow regulators, lubricants, glidants and mould release agents        (for example magnesium stearate, stearic acid, talc,        highly-disperse silicas (such as, for example, Aerosil®)),    -   coating materials (for example sugar, shellac) and film formers        for films or diffusion membranes which dissolve rapidly or in a        modified manner (for example polyvinylpyrrolidones (such as, for        example, Kollidon®), polyvinyl alcohol,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        ethylcellulose, hydroxypropylmethylcellulose phthalate,        cellulose acetate, cellulose acetate phthalate, polyacrylates,        polymethacrylates such as, for example, Eudragit®)),    -   capsule materials (for example gelatine,        hydroxypropylmethylcellulose),    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates (such as, for example,        Eudragit), polyvinylpyrrolidones (such as, for example,        Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene        oxides, polyethylene glycols and their copolymers and        blockcopolymers),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetine, triacetyl citrate, dibutyl        phthalate),    -   penetration enhancers,    -   stabilisers (for example antioxidants such as, for example,        ascorbic acid, ascorbyl palmitate, sodium ascorbate,        butylhydroxyanisole, butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, thiomersal,        benzalkonium chloride, chlorhexidine acetate, sodium benzoate),    -   colourants (for example inorganic pigments such as, for example,        iron oxides, titanium dioxide),    -   flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceuticalcomposition which comprise at least one compound according to theinvention, conventionally together with one or more pharmaceuticallysuitable excipient(s), and to their use according to the presentinvention.

In accordance with another aspect, the present invention providespharmaceutical combinations, in particular medicaments, comprising atleast one compound of general formula (I) of the present invention andat least one or more further active ingredients, in particular for thetreatment and/or prophylaxis of a hyperproliferative disorder,particularly cancer.

Particularly, the present invention provides a pharmaceuticalcombination, which comprises:

-   -   one or more first active ingredients, in particular compounds of        general formula (I) as defined supra, and    -   one or more further active ingredients, in particular        anti-cancer agents.

The term “combination” in the present invention is used as known topersons skilled in the art, it being possible for said combination to bea fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient, such as one or more compounds ofgeneral formula (I) of the present invention, and a further activeingredient are present together in one unit dosage or in one singleentity. One example of a “fixed combination” is a pharmaceuticalcomposition wherein a first active ingredient and a further activeingredient are present in admixture for simultaneous administration,such as in a formulation. Another example of a “fixed combination” is apharmaceutical combination wherein a first active ingredient and afurther active ingredient are present in one unit without being inadmixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a further activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the further active ingredient are present separately. Itis possible for the components of the non-fixed combination orkit-of-parts to be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention also provides suchpharmaceutical combinations. For example, the compounds of the presentinvention can be combined with known anti-cancer agents.

Examples of anti-cancer agents include:

131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumabemtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab,alendronic acid, alitretinoin, altretamine, amifostine,aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine,anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine,angiotensin II, antithrombin Ill, aprepitant, arcitumomab, arglabin,arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab,belotecan, bendamustine, besilesomab, belinostat, bevacizumab,bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab,bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan,cabazitaxel, cabozantinib, calcitonine, calcium folinate, calciumlevofolinate, capecitabine, capromab, carboplatin, carboquone,carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin,ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine,cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid,clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin,decitabine, degarelix, denileukin diftitox, denosumab, depreotide,deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron,doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab,edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin,enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa,epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib,esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide,everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine,lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin,levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin,lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol,melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone,methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin,nelarabine, neridronic acid, netupitant/palonosetron,nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab,nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide,ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin,oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel,palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronicacid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase,PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab,pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine,pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab,picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin,poliglusam, polyestradiol phosphate, polyvinylpyrrolidone+sodiumhyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium,pralatrexate, prednimustine, prednisone, procarbazine, procodazole,propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride,radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab,ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronicacid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin,romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam,sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran,sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol,streptozocin, sunitinib, talaporfin, talimogene laherparepvec,tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium(99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab,trastuzumab emtansine, treosulfan, tretinoin, trifluridine+tipiracil,trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin,tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide,vemurafenib, vinblastine, vincristine, vindesine, vinflunine,vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glassmicrospheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyperproliferative and/or inflammatorydisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown active ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of the presentinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from about 0.5 mg to about 1500 mg(e.g. about 0.5 mg to about 5 mg, about 5 mg to about 50 mg, about 50 mgto about 500 mg, about 500 mg to about 1500 mg, etc.) of activeingredient, and can be administered one or more times per day or lessthan once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. The average daily rectaldosage regimen will preferably be from 0.01 to 200 mg/kg of total bodyweight. The average daily vaginal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The average daily topical dosageregimen will preferably be from 0.1 to 200 mg administered between oneto four times daily. The transdermal concentration will preferably bethat required to maintain a daily dose of from 0.01 to 200 mg/kg. Theaverage daily inhalation dosage regimen will preferably be from 0.01 to100 mg/kg of total body weight.

In other embodiments of the invention the total amount of the activeingredient to be administered will generally range from 0.001 mg/kg to200 mg/kg body weight per day, and preferably from 0.01 mg/kg to 20mg/kg body weight per day. Clinically useful dosing schedules will rangefrom one to three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from 0.5 mg to 1500 mg of activeingredient, and can be administered one or more times per day or lessthan once a day.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

EXPERIMENTAL SECTION

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered.

The ¹H-NMR data of selected examples are listed in the form of ¹H-NMRpeaklists. For each signal peak the δ value in ppm is given, followed bythe signal intensity, reported in round brackets. The δ value-signalintensity pairs from different peaks are separated by commas. Therefore,a peaklist is described by the general form: δ₁ (intensity₁), δ₂(intensity₂), . . . , δ_(i) (intensity_(i)), . . . , δ_(n)(intensity_(n)).

The intensity of a sharp signal correlates with the height (in cm) ofthe signal in a printed NMR spectrum. When compared with other signals,this data can be correlated to the real ratios of the signalintensities. In the case of broad signals, more than one peak, or thecenter of the signal along with their relative intensity, compared tothe most intense signal displayed in the spectrum, are shown. A ¹H-NMRpeaklist is similar to a classical ¹H-NMR readout, and thus usuallycontains all the peaks listed in a classical NMR interpretation.Moreover, similar to classical ¹H-NMR printouts, peaklists can showsolvent signals, signals derived from stereoisomers of target compounds(also the subject of the invention), and/or peaks of impurities. Thepeaks of stereoisomers, and/or peaks of impurities are typicallydisplayed with a lower intensity compared to the peaks of the targetcompounds (e.g., with a purity of >90%). Such stereoisomers and/orimpurities may be typical for the particular manufacturing process, andtherefore their peaks may help to identify the reproduction of ourmanufacturing process on the basis of “by-product fingerprints”. Anexpert who calculates the peaks of the target compounds by known methods(MestReC, ACD simulation, or by use of empirically evaluated expectationvalues), can isolate the peaks of target compounds as required,optionally using additional intensity filters. Such an operation wouldbe similar to peak-picking in classical ¹H-NMR interpretation. Adetailed description of the reporting of NMR data in the form ofpeaklists can be found in the publication “Citation of NMR Peaklist Datawithin Patent Applications” (cf. Research Disclosure Database Number605005, 2014, 1 Aug. 2014, orhttp://www.researchdisclosure.com/searching-disclosures). In the peakpicking routine, as described in the Research Disclosure Database Number605005, the parameter “MinimumHeight” can be adjusted between 1% and 4%.Depending on the chemical structure and/or depending on theconcentration of the measured compound it may be reasonable to set theparameter “MinimumHeight”<1%.

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

The following table 1 lists the abbreviations used in this paragraph andin the Examples section as far as they are not explained within the textbody. Other abbreviations have their meanings customary per se to theskilled person.

TABLE 1 Abbreviations Abbreviation Meaning aq. aqueous ACN acetonitrilebr broad (¹H-NMR signal) cat. catalytic CDI 1,1′-carbonyldiimidazole CIchemical ionisation conc. concentrated d doublet DAD diode arraydetector DCM dichloromethane dd double-doublet ddddouble-doublet-doublet DIPEA diisopropylethylamine DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide eq. equivalent ESI electrospray (ES) ionisation h hour(s)HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate HBTU(o-benzotriazole-10-y1)-N,N,N′,N,-tetramethyluronium hexafluorophosphateHCI hydrochloric acid HPLC high performance liquid chromatography LC-MSliquid chromatography mass spectrometry m multiplet min minute(s) MeOHmethanol Mp. melting point MS mass spectrometry Abbreviation Meaning NMRnuclear magnetic resonance spectroscopy: chemical shifts (δ) are givenin ppm. The chemical shifts were corrected by setting the DMSO signal to2.50 ppm unless otherwise stated. MTP microtiter plate q quartet quinquintet r.t. or rt or RT room temperature Rt retention time (as measuredeither with HPLC or UPLC) in minutes s singlet sxt sextet sep septet ttriplet td triple-doublet THF tetrahydrofuran TLC thin-layerchromatography UPLC ultra performance liquid chromatography

Other abbreviations have their meanings customary per se to the skilledperson.

The various aspects and embodiments of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Experimental Section—General Part

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z)are reported from the positive mode electrospray ionisation unless thenegative mode is indicated (ESI−).

Method A (HPLC-MS):

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method B (HPLC-MS):

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 Vol-% aq. ammonia (32%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Experimental Section—Intermediates Intermediate 1 tert-butyl2,4,5-trifluorobenzoate

To stirred solution of 2,4,5-trifluorobenzoic acid (28.4 g, 161 mmol,1.00 eq.) in tert-butanol (806 mL, 0.20 mol/L) was successively addeddi-tert-butyl-dicarbonate (70.4 g, 323 mmol, 2.00 eq.) and DMAP (1.97 g,16.1 mmol, 0.10 eq.). The resulting mixture was stirred 30° C. overnightand concentrated under reduced pressure. The residue was diluted withethyl acetate and washed with aqueous 1.0 M hydrochloric acid (2×),saturated aqueous sodium bicarbonate (2×), brine (2×), dried (sodiumsulfate) and concentrated under reduced pressure.

The residue was purified by column chromatography (hexanes/ethylacetate) to give the desired product (27.4 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.58 (s, 9H), 6.91-7.02 (m, 1H), 7.71(ddd, 1H).

Triazolone Intermediates (IV)

Triazolones were obtained commercially or synthesized according to theliterature unless specified below.

The following intermediates can be synthesized using the proceduresoutlined in Chemische Berichte (1969), 102(3), 755-66:3-chloro-4-methyl-1H-1,2,4-triazol-5(4H)-one,3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one,

The following intermediates were previously described in Chimica actaTurcica (1975), Vol. 2, Issue 3, page 113:4-methyl-3-propyl-1H-1,2,4-triazol-5(4H)-one,3-ethyl-4-(2-hydroxyethyl)-1H-1,2,4-triazol-5(4H)-one

The following intermediates can be synthesized using the proceduresoutlined in EP 0422469 A2 (Example numbers refer to the originalpublication):

4-isopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-5),3-cyclopropyl-4-methyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-33),3-cyclopropyl-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-34),4-cyclopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-18),4-cyclopropyl-3-ethyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-24),3-isopropyl-4-methyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-13),4-cyclopentyl-3-methyl-1H-1,2,4-triazol-5(4H)-one (Ex. 11-46),3-cyclobutyl-4-methyl-1H-1,2,4-triazol-5(4H)-one,3-tert-butyl-4-methyl-1H-1,2,4-triazol-5(4H)-one,4-cyclopropylmethyl-3-methyl-1H-1,2,4-triazol-5(4H)-one,3,4-diethyl-1H-1,2,4-triazol-5(4H)-one,3-cyclopentyl-4-methyl-1H-1,2,4-triazol-5(4H)-one,4-butan-2-yl-3-methyl-1H-1,2,4-triazol-5(4H)-one,3-butan-2-yl-4-methyl-1H-1,2,4-triazol-5(4H)-one,

The following intermediates can be synthesized using the proceduresoutlined in DE 3709574 A1:3-dimethylamino-4-methyl-1H-1,2,4-triazol-5(4H)-one (Ex IV-1),3-[ethyl(methyl)amino]-4-methyl-1H-1,2,4-triazol-5(4H)-one.

4-methyl-3-methylsulfanyl-1H-1,2,4-triazol-5-one can be synthesizedusing the procedures outlined in U.S. Pat. No. 4,098,896.

4-methyl-5-(trifluoromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one can besynthesized using the procedures outlined in U.S. Pat. No. 5,508,420.

4-methyl-3-methylamino-1H-1,2,4-triazol-5-one can be synthesized usingthe procedures outlined in DE 3916208.

The following intermediates can be synthesized using the proceduresoutlined in DE 3934081: 3-methyl-4-propyl-1H-1,2,4-triazol-5-one,4-cyclopentyl-1H-1,2,4-triazol-5-one.

The following intermediates can be synthesized using the proceduresoutlined in EP 507171/DE 4110795:4-cyclopropyl-3-methoxy-1H-1,2,4-triazol-5(4H)-one (Ex. 11-5),4-methyl-3-phenoxy-1H-1,2,4-triazol-5(4H)-one (Ex. 11-3),

3-chloro-4-ethyl-1H-1,2,4-triazol-5(4H)-one can be synthesized using theprocedures outlined in EP 0425948/DE 3936622

4-ethyl-3-methylsulfanyl-1H-1,2,4-triazol-5-one can be synthesized usingthe procedures outlined in EP 431291/DE 3936623

4-ethyl-3-isopropoxy-1H-1,2,4-triazol-5(4H)-one can be synthesized usingthe procedures outlined in EP 703224/DE 4433968

Intermediate 2tert-butyl[(1R)-1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]carbamate

Methyl N-(tert-butoxycarbonyl)-D-alaninate (8.00 g, 39.4 mmol) wasdissolved in ethanol (10 mL), followed by hydrazine hydrate (20 mL, 410mmol). The mixture was stirred at 100° C. for 30 min (Caution! Useappropriate safety measures). The solvent was removed to obtaintert-butyl [(2R)-1-hydrazinyl-1-oxopropan-2-yl]carbamate (8.00 g, 39.4mmol).

The crude intermediate was dissolved in dichloromethane (50 ml) andtreated with triethylamine (7.6 ml, 54 mmol), 1,1′-Carbonyldiimidazol(8.40 g, 51.8 mmol). The mixture was stirred at room temperatureovernight. The mixture was washed with water, organic solvent was driedand concentrated to obtain tert-butyl[(1R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]carbamate

The crude intermediate was dissolved in methylamine solution (27 mL, 40%solution in water, 380 mmol) and the mixture was heated to refluxovernight. The solvent was removed to yield tert-butyl[(1R)-1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]carbamatewhich was sufficiently pure to be used for further reactions.

Intermediate 3 tert-butyl[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]carbamate

Synthesized from N-(tert-butoxycarbonyl)-glycine methyl esteranalogously to Intermediate 2.

Intermediate 45-[1-(1-ethoxyethoxy)ethyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Synthesized from ethyl 2-(1-ethoxyethoxy)propanoate (Bulletin of theChemical Society of Japan, 1987, vol. 60, p. 2127-2138) analogously toIntermediate 2.

Intermediate 55-[(benzyloxy)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Synthesized from methyl (benzyloxy)acetate analogously to Intermediate2.

Intermediate 64-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

2-hydroxyacetohydrazide (50.0 g, 555 mmol) was dissolved in water (125mL) and cooled to 0° C. Ethyl isocyanate (44 ml, 560 mmol) was added(very exotherm!) and the resulting mixture was stirred at roomtemperature overnight. The resulting suspension was treated with sodiumhydroxide solution (64 g, 50 wt % in water) (exotherm). The resultingsolution was heated to 95° C. overnight. The yellow reaction mixture wasneutralized with concentrated hydrochloric acid and the resulting cloudysolution was concentrated to dryness. The solids were triturated with amixture of dichloromethane and isopropanol (4:1, 750 mL), the solutionwas filtered off and concentrated to dryness again to yield ˜78 g ofcrude product. The product was recrystallized from ethyl acetate toyield the desired product (56.2 g, 71% yield).

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.156 (6.88), 1.174 (16.00), 1.192(7.02), 2.518 (0.48), 3.606 (2.02), 3.623 (6.84), 3.641 (6.79), 3.659(1.96), 4.316 (4.51), 5.540 (0.94).

Intermediate 73-(1-hydroxy-1-methyl-ethyl)-4-methyl-1H-1,2,4-triazol-5-one

Hydrazine Hydrate (201 g, 4.03 mol) was added dropwise to methyl2-hydroxy-2-methylpropanoate (500.0 g, 4.03 mol) over 2 h (exotherm!).The rate of addition was controlled to maintain a temperature between45-55° C. The mixture was slowly heated to 80° C. to distill offmethanol. The crude hydrazide was dissolved in water (500 mL) and cooledto 0° C. Methyl isocyanate (230 g, 4.03 mol) was added (very exotherm!)and the resulting mixture was stirred at room temperature overnight. Theresulting mixture was treated with sodium hydroxide solution (480 g, 50wt % in water, 6 mol) (exotherm). The resulting solution was heated to95° C. overnight. The yellow reaction mixture was neutralized withconcentrated hydrochloric acid (716 g, 30.6%, 6 mol). The resultingcloudy solution was heated to 80° C., filtered hot, and cooled to roomtemperature. The product crystallized directly from the solution toyield 470 g, 74% yield).

Mp. 186° C.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.43 (s, 6H) 3.28 (s, 3H) 5.47 (s, 1H)11.45 (s, 1H).

Intermediate 8 3-(hydroxymethyl)-4-methyl-1H-1,2,4-triazol-5-one

Hydrazine Hydrate (150 g, 3 mol) was added dropwise to butylhydroxyacetate (417 g, 3 mol) (exotherm!). The mixture was slowly heatedto 50° C. for 1 h. N-Butanol was azeotroped with water. The crudehydrazide was dissolved in water (750 mL) and cooled to −10° C. Methylisocyanate (171 g, 3 mol) was added (very exotherm!) and the resultingmixture was stirred at room temperature overnight. The resulting mixturewas treated with sodium hydroxide solution (360 g, 50 wt % in water, 4.5mol) (exotherm). The resulting solution was heated to 95° C. overnight.The reaction mixture was neutralized with concentrated hydrochloric acid(555 g, 30%, 4.5 mol). The resulting mixture was concentrated to drynessand extracted with DMF (1 L). The DMF was removed under vacuum and theproduct was crystallized from ethyleneglycol (700 mL) to yield 250 g,74% yield).

Mp. 144-145° C.

Intermediate 9 3-[(1S)-1-hydroxyethyl]-4-methyl-1H-1,2,4-triazol-5-one

Synthesized analogous to Intermediate 7 fromethyl-(2S)-hydroxypropanoate. The product crystallized directly from thesolution to yield 465 g, which was recrystallized again from water (400mL) to yield 438 g of product (contained 8,5% water, 70% yield).

Mp. 100-103° C.

Optical rotation (MeOH) 18.8°+/−0.09.

¹H NMR (400 MHz, DMSO-d6) Shift=11.47 (br s, 1H), 5.55 (br d, J=5.6 Hz,1H), 4.61 (quin, J=6.2 Hz, 1H), 3.17 (s, 3H), 1.38 (d, J=6.6 Hz, 3H).

Intermediate 105-[(dimethylamino)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Synthesized analogously to Intermediate 7. After neutralization theaqueous solution was concentrated and the product was extracted from theresulting solids with ethoxythanol. The solvent was removed and theproduct was distilled. The product was then re-crystallized from butylacetate.

Mp. 115° C.

Intermediate 115-(1-methoxyethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one, mixtureof stereoisomers

Synthesized analogously to Intermediate 7. After neutralization theaqueous solution was concentrated and the product was extracted from theresulting solids with butyl acetate and isopropanol. The solvent wasremoved and the product was distilled. The product was thenre-crystallized from butyl acetate.

Intermediate 12 5-[(1S)-1-(benzyloxy)ethyl]-1,3,4-oxadiazol-2(3H)-one

(2S)-2-(benzyloxy)propanehydrazide (synthesis is described inWO2010/71813, 7.10 g, 36.6 mmol) was dissolved in THF (43 ml), CDI (7.11g, 43.9 mmol) was added and the mixture was cooled to 0° C.Triethylamine (10 ml, 73 mmol) was added dropwise. The mixture wasstirred at room temperature overnight. The mixture was concentrated andpurified using silica gel chromatography (DCM/MeOH 0-50%) to yield thedesired intermediate (6.94 g, 86% yield).

¹H NMR (400 MHz, CHLOROFORM-d) b ppm 1.46 (d, 3H), 4.34 (q, 1H),4.41-4.50 (m, 1H), 4.52-4.60 (m, 1H), 7.17 (s, 1H), 7.19-7.31 (m, 4H).

Intermediate 135-[(1S)-1-(benzyloxy)ethyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

5-[(1S)-1-(benzyloxy)ethyl]-1,3,4-oxadiazol-2(3H)-one (Intermediate 12,6.94 g, 31.5 mmol) was dissolved in methylamine (27 ml, 40% in water,380 mmol) and stirred at 100° C. for 5 h. The mixture was concentratedto yield the desired product in sufficient purity (7.4 g).

LC-MS (Method A): Rt=0.85 min, MS (ESIpos): m/z=234 [M+H]⁺

Intermediate 14 tert-butyl2,5-difluoro-4-(4-isopropyl-3-methyl-5-oxo-1,2,4-triazol-1-yl)benzoate

To a stirred solution of tert-butyl 2,4,5-trifluorobenzoate (4.99 g,21.5 mmol, 1.00 eq.) and 4-isopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one(3.19 g, 22.6 mmol, 1.05 eq.) in anhydrous acetonitrile (53.8 mL, 0.40mol/L) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.89 mL, 25.8 mmol,1.20 eq.). The resulting mixture was heated at 80° C. overnight, cooledto room temperature and concentrated under reduced pressure. The residuewas purified by column chromatography (hexanes/ethyl acetate) to givethe desired product (4.56 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.54 (d, 6H), 1.59 (s, 9H), 2.35 (s,3H), 4.32 (sep, 1H), 7.47 (dd, 1H), 7.69 (dd, 1H).

MS (ESIpos): m/z=354 (M+H)⁺.

Intermediate 15 tert-butyl4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonate wasused as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

Intermediate 16 tert-butyl4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from3-cyclopropyl-4-methyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonatewas used as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.29 min, MS (ESIpos): m/z=352 [M+H]⁺.

Intermediate 17 tert-butyl4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from3-cyclopropyl-4-ethyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonatewas used as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.37 min; MS (ESIpos): m/z=366 [M+H]⁺.

Intermediate 18 tert-butyl4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from4-cyclopropyl-3-methyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonatewas used as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.25 min; MS (ESIpos): m/z=352 [M+H]⁺.

Intermediate 19 tert-butyl4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from4-cyclopropyl-3-ethyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonatewas used as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.32 min; MS (ESIpos): m/z=366 [M+H]⁺.

Intermediate 20 tert-butyl4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from3-cyclobutyl-4-methyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonatewas used as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.39 min; MS (ESIpos): m/z=366 [M+H]⁺.

Intermediate 21 tert-butyl2,5-difluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate

Synthesized analogously to Intermediate 14 from4-methyl-5-(trifluoromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.39 min; MS (ESIpos): m/z=324 [M+H-tBu]⁺.

Intermediate 22 tert-butyl2,5-difluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate

Synthesized analogously to Intermediate 14 from3-isopropyl-4-methyl-1H-1,2,4-triazol-5(4H)-one. Potassium carbonate wasused as a base instead of 1,8-diazabicyclo[5.4.0]undec-7-ene.

LC-MS (Method A): R_(t)=1.34 min, MS (ESIpos): m/z=354 [M+H]⁺.

Intermediate 23 tert-butyl4-{3-[(1S)-1-(benzyloxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from Intermediate 13.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene.

¹H NMR (400 MHz, CHLOROFORM-d) 5=7.72 (dd, J=6.3, 10.6 Hz, 1H), 7.43(dd, J=5.8, 10.6 Hz, 1H), 7.40-7.27 (m, 5H), 4.63 (q, J=6.8 Hz, 1H),4.59-4.48 (m, 2H), 3.39 (s, 3H), 1.64 (d, J=6.8 Hz, 3H), 1.60 (s, 9H).

Intermediate 24 tert-butyl4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate,Mixture of Diastereomers

Synthesized analogously to Intermediate 14 from Intermediate 4.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene.

Intermediate 25 tert-butyl4-(3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from Intermediate 2.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene. DMF was used as solvent instead ofacetonitrile.

Intermediate 26 tert-butyl4-{3-[(benzyloxy)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from Intermediate 5.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene. DMF was used as solvent instead ofacetonitrile.

Intermediate 27 tert-butyl4-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

Synthesized analogously to Intermediate 14 from Intermediate 3.Potassium carbonate was used as a base instead of1,8-diazabicyclo[5.4.0]undec-7-ene. DMF was used as solvent instead ofacetonitrile.

Intermediate 28 tert-butyl4-(3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate

tert-butyl4-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate(Intermediate 27, 400 mg, 908 μmol) was dissolved in DMF (10 mL). Sodiumhydride (60% in mineral oil, 54.5 mg, 1.36 mmol), was added and themixture was stirred at room temperature for 15 min. Methyl iodide (193mg, 1.36 mmol) was added and the mixture was stirred at room temperaturefor 15 min. The reaction was quenched with brine (20 ml), extracted withethyl acetate (2×20 ml), washed with brine (2×20 ml), dried andconcentrated. The compound was purified using silica gel columnchromatography (petrol ether:ethyl acetate 5:1) to yield the desiredintermediate (150 mg, 36% yield).

Intermediate 29 tert-butyl4-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate,Salt with Hydrochloric Acid

tert-butyl4-(3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate(Intermediate 25, 1.80 g, 3.96 mmol) was dissolved in THF (30 ml).Hydrogen chloride gas was bubbled through the solution for 30 minutes.The reaction mixture was stirred at room temperature for another 2 h.The mixture was concentrated to yield the desired product in sufficientpurity (1.4 g, 90% yield).

Intermediate 30 tert-butyl4-{3-[(1R)-1-(dibenzylamino)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate

tert-butyl4-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoatehydrochloride (1:1) (Intermediate 29, 1.40 g, 3.58 mmol) was dissolvedin DMF (30 ml). Sodium hydride (640 mg, 60% in mineral oil, 16.0 mmol)was added slowly. The mixture was cooled to 0° C. and benzyl bromide(1.2 ml, 9.9 mmol) was added dropwise. The mixture was stirred at roomtemperature overnight, quenched with ammonium chloride solution (300ml), and extracted with ethyl acetate (200 ml). The organic layer waswashed with 200 ml brine. Column chromatography (petrol ether:ethylacetate 10:1) yields the product (800 mg, 41% yield).

Intermediate 31 tert-butyl4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

(2S)-1,1,1-trifluoropropan-2-ol (520 μl, 5.8 mmol) was dissolved in THF(5.8 mL) and cooled to −10° C. Potassium bis(trimethylsilyl)amide (1Msolution in THF, 3.2 ml, 3.2 mmol) was added dropwise and the mixturewas stirred at −10° C. for 1 h. tert-butyl4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzoate(Intermediate 16, 926 mg, 2.64 mmol) was added as a solution in THF (2.6mL). The mixture was slowly warmed to room temperature and stirred atroom temperature overnight. The reaction was quenched with water and themixture was extracted with DCM. The aqueous layer was extracted oncemore with water and the combined organic layers were washed with brine.The resulting solution was dried over magnesium sulfate and concentratedto yield the desired product (888 mg, 76% yield).

LC-MS (Method A.): R_(t)=1.40 min; MS (ESIpos): m/z=446 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.000 (0.64), 1.384 (1.34), 1.400(1.41), 1.479 (0.87), 1.500 (16.00), 3.303 (5.18), 3.322 (13.59), 7.563(0.83), 7.588 (0.79).

Intermediate 32 tert-butyl4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 20 and(2S)-1,1,1-trifluoropropan-2-ol

LC-MS (Method A): R_(t)=1.47 min; MS (ESIpos): m/z=460 [M+H]⁺.

Intermediate 33 tert-butyl4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 18 and(2S)-1,1,1-trifluoropropan-2-ol.

Intermediate 34 tert-butyl4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 19 and(2S)-1,1,1-trifluoropropan-2-ol.

Intermediate 35 tert-butyl4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 17 and(2S)-1,1,1-trifluoropropan-2-ol.

Intermediate 36 tert-butyl5-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 21 and(2S)-1,1,1-trifluoropropan-2-ol.

LC-MS (Method A): R_(t)=1.49 min, MS (ESIpos): m/z=418 [M+H-tBu]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.404 (1.48), 1.420 (1.48), 1.510(16.00), 3.382 (2.80), 7.669 (0.85), 7.694 (0.84).

Intermediate 37 tert-butyl5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 22 and(2S)-1,1,1-trifluoropropan-2-ol.

The crude product was triturated with a 1:1 mixture of water andethanol, washed with water and dried in a vacuum oven.

LC-MS (Method A): R_(t)=1.42 min; MS (ESIpos): m/z=392 [M+H-tBu]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.239 (4.32), 1.256 (4.42), 1.401(1.43), 1.417 (1.43), 1.514 (16.00), 1.546 (0.64), 3.261 (5.15), 7.587(0.85), 7.613 (0.82).

Intermediate 38 tert-butyl4-{3-[(1S)-1-(benzyloxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate

Synthesized analogously to Intermediate 31 from Intermediate 23 and(2S)-1,1,1-trifluoropropan-2-ol.

LC-MS (Method A): Rt=1.52 min; MS (ESIpos): m/z=540 [M+H]⁺.

Intermediate 395-fluoro-4-(4-isopropyl-3-methyl-5-oxo-1,2,4-triazol-1-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]benzoicAcid

To a −10° C. stirred solution of (S)-1,1,1-trifluoropropan-2-ol (702 mg,6.15 mmol, 2.05 eq.) in anhydrous THF (6.15 mL, 1.00 mol/L) was added a1.0 M solution of potassium hexamethyldisilazide in THF (3.30 mL, 3.30mmol, 1.10 eq.) dropwise. The mixture was stirred at −10° C. for 1 h,after which the mixture was added dropwise to a −10° C. stirred solutionof tert-butyl2,5-difluoro-4-(4-isopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate(1.06 g, 3.00 mmol, 1.00 eq.). The solution was stirred for 2 h at −10°C. followed by 2 days at room temperature and then concentrated underreduced pressure. Following column chromatography (hexanes/ethylacetate), the residue was resuspended in a 4:1 mixture of dioxane:water(15.0 mL, 0.20 mol/L) and lithium hydroxide (1.08 g, 45.0 mmol, 15.0eq.) was added. The resulting suspension was stirred at 70° C. for 2 dand cooled to room temperature. Water was added to the mixture wandwashed with diethyl ether (2×). The aqueous layer was acidified to pH 2with 1.0 M aqueous hydrochloric acid and extracted with diethyl ether(3×). The combined organic extracts were washed with brine, dried(magnesium sulfate) and concentrated under reduced pressure. The residuewas purified by column chromatography (dicloromethane/methanol) to givethe desired product (957 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.63 (d, 3H), 2.37 (s,3H), 4.32 (sep, 1H), 4.89 (q, 1H), 7.53 (d, 1H), 8.00 (d, 1H).

MS (ESIpos): m/z=392 (M+H)⁺.

Intermediate 404-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoro-propan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 15 and(S)-1,1,1-trifluoropropan-2-ol.

LC-MS (Method A): R_(t)=0.93 min, MS (ESIpos): m/z=378.5 [M+H]⁺.

Intermediate 415-fluoro-4-(4-isopropyl-3-methyl-5-oxo-1,2,4-triazol-1-yl)-2-[(1S)-1-phenylethoxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 14 and(1S)-1-phenylethanol.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.53 (d, 3H), 1.80 (d, 3H), 2.33 (s,3H), 4.30 (sep, 1H), 5.61 (q, 1H), 7.30-7.40 (m, 5H), 7.45 (d, 1H), 7.97(d, 1H), 11.1 (b, 1H).

MS (ESIpos): m/z=400 (M+H)⁺.

Intermediate 425-fluoro-4-(4-isopropyl-3-methyl-5-oxo-1,2,4-triazol-1-yl)-2-[(1S)-1-methylbutoxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 14 and(2S)-pentan-2-ol.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.97 (t, 3H), 1.37-1.54 (m, 2H), 1.44(d, 3H), 1.55 (d, 6H), 1.64-1.92 (m, 2H), 2.37 (s, 3H), 4.33 (sep, 1H),4.64-4.77 (m, 1H), 7.45 (d, 1H), 8.01 (d, 1H), 11.1 (b, 1H).

MS (ESIpos): m/z=366 (M+H)⁺.

Intermediate 434-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 15 and(1S)-1-phenylethanol.

LC-MS (Method A): R_(t)=1.03 min.

MS (ESIpos): m/z=386 [M+H]⁺.

Intermediate 444-(3-ethyl-4-methyl-5-oxo-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-methylbutoxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 15 and(2S)-pentan-2-ol.

¹H NMR (400 MHz, CDCl₃) δ [ppm] 0.97 (t, 3H), 1.35 (t, 3H), 1.39-1.58(m, 2H), 1.43 (d, 3H), 1.66-1.77 (m, 1H), 1.79-1.91 (m, 1H), 2.64 (q,2H), 3.32 (s, 3H), 4.64-4.73 (m, 1H), 7.43 (d, 1H), 8.02 (d, 1H), 11.1(b, 1H).

MS (ESIpos): m/z=352 (M+H)⁺.

Intermediate 454-(3-ethyl-4-methyl-5-oxo-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-methylbutoxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 22 and(2S)-pentan-2-ol using sodium hydride as a base and DMF as the solvent.

Intermediate 464-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pent-4-en-2-yloxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 15 and(2S)-pent-4-en-2-ol using sodium hydride as a base and DMF as thesolvent.

Intermediate 472-(1-cyclohexylethoxy)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoicAcid, Mixture of Stereoisomers

Synthesized analogously to Intermediate 39 from Intermediate 24 and1-cyclohexylethanol using sodium hydride as a base and DMF as thesolvent.

Intermediate 484-{3-[(benzyloxy)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-(1-cyclohexylethoxy)-5-fluorobenzoicAcid, Mixture of Stereoisomers

Synthesized analogously to Intermediate 39 from Intermediate 26 and1-cyclohexylethanol using sodium hydride as a base and DMF as thesolvent.

Intermediate 494-(3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 28 and(2S)-pentan-2-ol using sodium hydride as a base and DMF as the solvent.

Intermediate 504-{3-[(dibenzylamino)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 30 and(2S)-pentan-2-ol using sodium hydride as a base and DMF as the solvent.

MS: m/z=533 (M+H)⁺.

Intermediate 514-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoicAcid, Mixture of Stereoisomers

Synthesized analogously to Intermediate 39 from Intermediate 24 and(2S)-pentan-2-ol using sodium hydride as a base and DMF as the solvent.

Intermediate 522-(1-cyclohexylethoxy)-4-{3-[(1R)-1-(dibenzylamino)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoicAcid, Mixture of Stereoisomers

tert-butyl4-{3-[(1R)-1-(dibenzylamino)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluorobenzoate(Intermediate 30, 334 mg, 625 μmol) and (1S)-1-cyclohexylethanol (130mg, 1.12 mmol) were dissolved in DMF (10 ml), sodium hydride (45.0 mg,60% in mineral oil, 1.12 mmol) was added, and the mixture was stirred at100° C. for 6 h. The solvent was removed and the product was purifiedusing prepTLC to yield 120 mg (60% yield).

Intermediate 534-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

tert-butyl4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoate(Intermediate 35, 3.84 g, 8.36 mmol) was dissolved in dichloromethane(12 ml). Trifluoroacetic acid (12 ml, 160 mmol) was added dropwise andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated and the crude product was purified by columnchromatography (dicloromethane/methanol) to give the desired product(2.02 g, 60% yield).

LC-MS (Method A): R_(t)=1.06 min, MS (ESIpos): m/z=404 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.761 (0.65), 0.766 (0.71), 0.779(0.69), 0.866 (0.78), 0.887 (2.00), 0.898 (4.51), 0.904 (5.19), 0.911(4.78), 0.916 (4.67), 0.925 (1.99), 0.976 (1.92), 0.984 (4.42), 0.991(3.32), 0.996 (2.93), 1.005 (4.74), 1.011 (3.26), 1.023 (1.17), 1.165(1.17), 1.184 (2.45), 1.201 (1.21), 1.260 (7.20), 1.278 (16.00), 1.296(7.20), 1.394 (12.36), 1.410 (12.63), 1.422 (1.25), 1.469 (0.96), 1.486(0.95), 1.996 (0.78), 2.009 (1.52), 2.017 (1.65), 2.029 (2.86), 2.038(1.16), 2.042 (1.56), 2.050 (1.36), 2.063 (0.62), 2.326 (0.75), 2.522(2.24), 2.668 (0.79), 3.654 (1.12), 3.671 (1.09), 3.787 (2.10), 3.805(6.60), 3.823 (6.47), 3.841 (1.95), 5.190 (0.84), 5.206 (2.04), 5.222(2.61), 5.238 (1.94), 5.253 (0.87), 5.757 (0.82), 7.466 (4.81), 7.481(4.73), 7.621 (5.56), 7.648 (5.36).

Intermediate 544-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 31.

LC-MS (Method A): R_(t)=1.98 min; MS (ESIpos): m/z=390 [M+H]⁺.

¹H-NMR (500 MHz, DMSO-d6) δ[ppm]: 0.874 (1.67), 0.884 (5.75), 0.888(6.08), 0.893 (5.75), 0.898 (6.38), 0.905 (2.85), 0.966 (2.38), 0.974(6.11), 0.979 (4.77), 0.983 (3.45), 0.990 (6.25), 0.995 (4.79), 1.005(1.73), 1.038 (2.63), 1.052 (5.18), 1.066 (2.47), 1.234 (1.15), 1.291(1.86), 1.305 (3.84), 1.320 (1.73), 1.395 (15.07), 1.408 (16.00), 1.420(0.93), 1.471 (0.74), 1.484 (0.71), 1.508 (0.88), 1.957 (1.10), 1.967(2.05), 1.974 (2.30), 1.977 (1.23), 1.984 (4.03), 1.990 (1.40), 1.994(1.97), 2.000 (2.03), 2.010 (0.93), 2.514 (7.45), 2.518 (6.08), 2.522(4.52), 3.159 (1.01), 3.275 (0.82), 3.416 (0.99), 3.430 (2.88), 3.444(2.77), 3.457 (0.93), 3.857 (2.96), 4.398 (0.58), 4.412 (1.42), 4.426(1.34), 5.182 (0.93), 5.194 (2.27), 5.207 (3.10), 5.220 (2.19), 5.233(0.85), 5.758 (2.14), 7.454 (6.19), 7.466 (6.19), 7.633 (7.34), 7.654(6.99).

Intermediate 554-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 32.

LC-MS (Method A): R_(t)=1.08 min; MS (ESIpos): m/z=404 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.405 (4.83), 1.421 (4.84), 1.515(0.81), 1.531 (4.45), 2.046 (0.89), 2.068 (0.80), 2.073 (0.81), 2.292(2.66), 2.301 (1.18), 2.304 (1.38), 2.313 (3.23), 2.327 (1.01), 2.331(1.15), 2.334 (1.16), 2.338 (0.93), 3.138 (16.00), 3.597 (0.80), 3.599(0.84), 3.618 (1.18), 3.620 (1.26), 3.638 (0.74), 3.641 (0.79), 5.213(0.89), 5.229 (1.13), 5.245 (0.83), 7.511 (2.12), 7.526 (2.10), 7.652(2.70), 7.678 (2.58).

Intermediate 564-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 33.

LC-MS (Method A): R_(t)=0.95 min; MS (ESIpos): m/z=389 [M+H]⁺.

Intermediate 575-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 36.

LC-MS (Method A): R_(t)=1.11 min; MS (ESIpos): m/z=418 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.09), 1.406 (8.28), 1.421(8.32), 1.510 (0.82), 1.522 (3.20), 2.510 (1.29), 2.514 (0.89), 3.382(16.00), 5.177 (0.57), 5.193 (1.41), 5.209 (1.84), 5.225 (1.33), 5.747(0.96), 6.957 (1.06), 7.085 (1.16), 7.213 (1.05), 7.574 (3.58), 7.590(3.55), 7.716 (4.50), 7.741 (4.39).

Intermediate 584-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 34.

LC-MS (Method A): R_(t)=1.04 min; MS (ESIpos): m/z=403 [M+H]⁺.

Intermediate 595-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 37.

LC-MS (Method A): R_(t)=1.03 min; MS (ESIpos): m/z=392 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.171 (0.92), 1.224 (3.60), 1.232(1.87), 1.237 (15.86), 1.249 (2.00), 1.254 (16.00), 1.403 (4.62), 1.418(4.66), 1.735 (1.21), 1.986 (1.58), 2.083 (1.04), 3.015 (1.16), 3.032(1.58), 3.050 (1.12), 3.254 (1.33), 5.204 (0.80), 5.220 (1.04), 5.237(0.74), 5.756 (0.69), 7.492 (2.08), 7.507 (2.06), 7.648 (2.70), 7.674(2.59), 8.132 (4.73).

Intermediate 604-{3-[(1S)-1-(benzyloxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

Synthesized analogously to Intermediate 53 from Intermediate 38.

LC-MS (Method A): R_(t)=1.21 min; MS (ESIpos): m/z=484 [M+H]⁺.

Intermediate 615-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

4-{3-[(1S)-1-(benzyloxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicacid (Intermediate 60, 866 mg, 1.79 mmol) was dissolved in ethanol (20mL). Palladium (10% on carbon, 191 mg, 179 μmol) and ammonium formate(1.69 g, 26.9 mmol) was added and the mixture was stirred at 80° C. for3 h. The mixture was filtered and concentrated. The residue was purifiedby flash column chromatography (DCM/MeOH 0-90%) to yield the desiredproduct (540 mg, 76% yield).

LC-MS (Method A): R_(t)=0.80 min; MS (ESIpos): m/z=394 [M+H]⁺.

Intermediate 624-bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzonitrile

To a stirred suspension of 4-bromo-2,5-difluorobenzonitrile (91 g, 417mmol) and potassium carbonate (173 g, 1.25 mol) in N,N-dimethylformamide(910 ml) was added (S)-1,1,1-trifluoropropanol [CAS 3539-97-7] dropwise(52.4 g, 460 mmol). The resulting mixture was heated at 70° C. for 15hours and cooled to room temperature. The reaction was concentrated andthe residue was diluted with water. The aqueous solution was extractedwith DCM (3×). The combined organic washes were washed with brine, driedover sodium sulfate, filtered, and concentrated under reduced pressureto give an oil (136.6 g). The residue was triturated with a mixture ofhexanes and toluene (9:1, 200 mL) to give the desired product as a whitesolid (90.3 g, 93% purity, 64% yield).

LC-MS (Method A): R_(t)=1.29 min, MS (ESIpos): m/z=312.0 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.511 (4.41), 1.531 (15.64),1.533 (16.00), 1.548 (15.84), 1.550 (15.83), 4.566 (1.08), 4.581 (2.68),4.597 (3.18), 4.612 (2.62), 4.626 (1.01), 7.194 (5.27), 7.207 (7.60),7.220 (7.57).

Intermediate 63 4-bromo-5-fluoro-2-[(2S)-pentan-2-yloxy]benzonitrile

Synthesized analogously to Intermediate 62 from4-bromo-2,5-difluorobenzonitrile and (S)-2-pentanol.

¹H NMR (400 MHz, DMSO-d6) 5=7.92 (d, J=8.1 Hz, 1H), 7.70 (d, J=5.6 Hz,1H), 4.70 (sxt, J=6.0 Hz, 1H), 1.71-1.49 (m, 2H), 1.46-1.31 (m, 2H),1.25 (d, J=5.8 Hz, 3H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 644-bromo-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzonitrile

Synthesized analogously to Intermediate 62 from4-bromo-2-fluorobenzonitrile and (S)-1,1,1-trifluoropropanol.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIpos): m/z=294 [M+H]⁺.

¹H-NMR (500 MHz, CHLOROFORM-d) δ [ppm]: 1.368 (3.65), 1.415 (15.76),1.427 (16.00), 1.428 (15.81), 1.984 (0.94), 4.525 (1.13), 4.538 (2.65),4.550 (3.35), 4.562 (2.58), 4.574 (1.03), 7.019 (7.92), 7.022 (8.28),7.073 (9.59), 7.089 (5.49), 7.092 (5.57), 7.105 (7.20), 7.108 (6.95).

Intermediate 654-bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoic Acid

To a solution of4-bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzonitrile(Intermediate 62, 27.4 g, 87.9 mmol) in ethanol (90 ml) was addedaqueous sodium hydroxide (2 N, 140 ml) and the resulting mixture washeated to 90° C. for 20 hours. The resulting solution was cooled to roomtemperature, diluted with water, and extracted with dichloromethane. Theaqueous phase was acidified with 2 N aqueous hydrochloric acid (pH 2)upon which a white solid precipitated. The suspension was stirred forfurther 15 minutes, the solid was filtered off, washed with water anddried in vacuo. to yield an off-white solid (25.97 g, 89%), which wasused for the next step without further purification.

LC-MS (Method A): R_(t)=1.16 min; MS (ESIpos): m/z=331 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.396 (15.96), 1.411 (16.00), 1.469(0.69), 1.484 (0.45), 2.518 (3.48), 2.523 (2.36), 5.288 (1.19), 5.304(2.89), 5.320 (3.73), 5.336 (2.70), 5.352 (1.05), 7.612 (11.35), 7.634(11.12), 7.743 (7.88), 7.757 (7.91).

Intermediate 66 4-bromo-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoic Acid

Synthesized analogously to Intermediate 65 from Intermediate 63.

LC-MS (Method A): R_(t)=1.33 min, MS (ESIneg): m/z=303 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.858 (6.86), 0.876 (16.00), 0.894(8.19), 1.192 (14.64), 1.208 (14.81), 1.322 (0.52), 1.339 (1.03), 1.346(0.95), 1.363 (2.02), 1.381 (2.40), 1.397 (2.08), 1.418 (1.35), 1.437(0.69), 1.464 (0.71), 1.478 (0.92), 1.486 (0.48), 1.497 (1.30), 1.512(1.59), 1.520 (1.07), 1.526 (1.00), 1.534 (1.18), 1.549 (0.63), 1.570(0.87), 1.585 (1.27), 1.594 (0.98), 1.600 (1.20), 1.609 (1.21), 1.619(0.91), 1.624 (0.96), 1.633 (0.59), 1.643 (0.65), 4.519 (1.19), 4.534(2.20), 4.549 (2.18), 4.564 (1.14), 7.466 (4.77), 7.480 (4.70), 7.524(5.49), 7.545 (5.40).

Intermediate 67 4-bromo-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicAcid

To a solution of4-bromo-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzonitrile(Intermediate 64, 5.00 g, 17.0 mmol) in ethanol (18 ml) was addedaqueous sodium hydroxide (2 N, 28 ml) and the resulting mixture washeated to 90° C. for 21 hours. The resulting solution was cooled to roomtemperature, diluted with water, and extracted with dichloromethane. Theaqueous phase was acidified with 2 N aqueous hydrochloric acid (pH 2)upon which a white solid precipitated. The suspension was stirred forfurther 15 minutes, the solid was filtered off, washed with water anddried in vacuo. to yield white solid 4.76 g (89%), which was used forthe next step without further purification.

LC-MS (Method A): R_(t)=1.15 min; MS (ESIneg): m/z=311 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.403 (15.87), 1.419 (16.00), 2.518(2.74), 2.523 (1.80), 5.352 (1.13), 5.368 (2.86), 5.383 (3.71), 5.400(2.72), 5.416 (1.03), 7.299 (6.49), 7.304 (6.51), 7.320 (6.97), 7.324(7.05), 7.584 (13.85), 7.596 (8.97), 7.600 (8.84), 7.605 (12.52).

Intermediate 684-bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoylChloride

To a solution of4-bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoic Acid(Intermediate 65, 15.0 g, 45.3 mmol) in dichloromethane (230 ml) wasadded N,N-dimethylformamide (350 μl), followed by dropwise addition ofethanedioyl dichloride (4.7 ml, 54 mmol). The reaction mixture wasstirred at room temperature for one hour, and concentrated under reducedpressure. The title compound was obtained as brown oil (15.84 g,quantitative), which was used for the next step without purification.For analytic, a small amount of the product was treated with methanol,to yield the corresponding methyl ester, which was detected by LC-MS.

LC-MS (Method A) [methyl ester]: R_(t)=1.36 min; MS (ESIpos): m/z=345[M+H]⁺.

Intermediate 69 4-bromo-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoylChloride

To a solution of 4-bromo-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicacid (2.6 g, 8.3 mmol) in dichloromethane (42 ml) was addedN,N-dimethylformamide (870 μl), followed by dropwise addition ofethanedioyl dichloride (870 μl, 10 mmol). The reaction mixture wasstirred at room temperature for one hour, and concentrated under reducedpressure. The title compound was obtained as brown oil (15.84 g,quantitative), which was used for the next step without purification.For analytic, a small amount of the product was treated with methanol,to yield the corresponding methyl ester, which was detected by LC-MS.

LC-MS (Method A) [methyl ester]: R_(t)=1.33 min; MS (ESIpos): m/z=327[M+H]⁺.

Intermediate 704-bromo-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoylchloride (Intermediate 68, 17.0 g, 48.6 mmol) was dissolved in DCM (200mL) and added to a solution of 2,6-difluoroaniline (5.8 ml, 54 mmol) andtriethylamine (7.5 ml, 54 mmol) in DCM (350 mL). The mixture was stirredat room temperature for 1 h. The mixture was concentrated to yield 29.3g of crude product. The crude product was dissolved in ethanol (150 mL)and water (300 mL) was added slowly. The resulting precipitate wasfiltered off, the solids were washed with water and dried to yield thedesired product (20.6 g, 96% yield).

LC-MS (Method A): R_(t)=1.40 min; MS (ESIneg): m/z=440 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.147 (1.01), 1.165 (1.91), 1.184(1.01), 1.339 (0.56), 1.356 (0.62), 1.394 (0.97), 1.411 (1.35), 1.430(16.00), 1.446 (15.69), 1.486 (0.42), 2.331 (0.97), 2.518 (4.44), 2.522(3.02), 2.673 (0.97), 5.366 (1.11), 5.383 (2.64), 5.399 (3.30), 5.415(2.46), 5.430 (1.04), 7.183 (4.93), 7.203 (10.41), 7.224 (6.52), 7.367(1.18), 7.382 (2.50), 7.403 (3.68), 7.419 (1.98), 7.424 (1.91), 7.440(0.83), 7.555 (7.05), 7.576 (6.98), 7.808 (6.25), 7.822 (6.18), 9.886(0.42), 9.918 (10.17).

Intermediate 714-bromo-N-(2-chloro-6-fluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoylchloride (Intermediate 68, 31.9 g, 91.3 mmol) was dissolved in DCM (300mL) and added to a solution of 2-chloro-6-fluoroaniline (14.6 g, 100.4mmol) and triethylamine (14 ml, 100 mmol) in DCM (400 mL). The mixturewas stirred at room temperature for 30 min. The mixture was concentratedto yield 47.9 g of crude product. The crude product was dissolved inethanol (250 mL) and water (500 mL) was added slowly. The resultingprecipitate was filtered off, the solids were washed with water anddried to yield the desired product (39.3 g, 84.5% yield).

Synthesized analogously to Intermediate 70 from Intermediate 68 and2-chloro-6-fluoroaniline.

LC-MS (Method A): R_(t)=1.44 min, MS (ESIpos): m/z=458 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.343 (1.46), 1.359 (1.66), 1.387(0.50), 1.437 (16.00), 1.452 (15.88), 1.475 (0.73), 1.495 (0.82), 1.513(0.53), 1.907 (0.67), 2.332 (1.23), 2.518 (7.59), 2.523 (4.64), 2.673(1.20), 5.400 (1.28), 5.416 (2.77), 5.432 (3.47), 5.448 (2.51), 5.464(1.02), 7.323 (1.55), 7.328 (1.69), 7.347 (3.94), 7.354 (2.01), 7.363(2.31), 7.371 (2.98), 7.383 (2.19), 7.395 (1.78), 7.402 (3.88), 7.416(5.31), 7.425 (9.08), 7.431 (9.78), 7.445 (2.16), 7.481 (0.67), 7.502(0.44), 7.528 (6.83), 7.549 (6.80), 7.665 (0.44), 7.680 (0.70), 7.694(0.41), 7.820 (5.90), 7.833 (5.87), 9.977 (11.65).

Intermediate 724-bromo-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 68 and2-methoxy-4-methylpyridin-3-amine.

LC-MS (Method A): R_(t)=1.38 min; MS (ESIpos): m/z=451 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.446 (5.62), 1.462 (5.58), 2.200(13.29), 3.850 (16.00), 5.449 (0.89), 5.465 (1.15), 5.481 (0.85), 6.924(2.33), 6.937 (2.44), 7.546 (2.69), 7.568 (2.65), 7.799 (2.29), 7.813(2.29), 7.962 (2.81), 7.975 (2.74), 9.581 (2.51).

Intermediate 734-bromo-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 68 and2-fluoro-6-methylaniline

LC-MS (Method A): R_(t)=1.43 min; MS (ESIneg): m/z=436 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.430 (6.96), 1.446 (6.97), 2.253(16.00), 2.306 (0.44), 2.518 (1.84), 2.523 (1.21), 5.408 (0.47), 5.424(1.14), 5.441 (1.50), 5.456 (1.11), 5.473 (0.45), 7.093 (0.94), 7.109(2.52), 7.113 (2.43), 7.126 (2.63), 7.135 (1.55), 7.222 (1.09), 7.236(1.25), 7.241 (1.61), 7.256 (1.27), 7.261 (0.81), 7.275 (0.64), 7.538(4.25), 7.559 (4.17), 7.802 (3.13), 7.816 (3.11), 9.747 (3.41).

Intermediate 744-bromo-N-(2,6-dichlorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 68 and2,6-dichloroaniline. The product was purified using reverse phasechromatography.

LC-MS (Method A): R_(t)=1.47 min; MS (ESIpos): m/z=473 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.435 (14.34), 1.451 (14.01), 2.084(7.26), 2.323 (1.25), 2.327 (1.62), 2.332 (1.20), 2.518 (6.10), 2.523(3.75), 2.665 (1.16), 2.669 (1.53), 2.673 (1.11), 5.421 (1.02), 5.437(2.36), 5.453 (3.01), 5.469 (2.17), 5.485 (0.83), 7.376 (2.87), 7.397(4.86), 7.417 (3.98), 7.497 (7.26), 7.518 (7.31), 7.572 (16.00), 7.592(11.84), 7.818 (5.18), 7.832 (5.04), 10.140 (6.89).

Intermediate 754-bromo-N-(2,6-difluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 69 and2,6-difluoroaniline LC-MS (Method A): R_(t)=1.36 min, MS (ESIpos):m/z=424 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.054 (0.42), 1.350 (0.40), 1.365(0.42), 1.445 (16.00), 1.461 (15.92), 2.518 (4.30), 2.523 (2.73), 5.433(1.17), 5.449 (2.71), 5.465 (3.50), 5.481 (2.57), 5.497 (1.09), 7.176(4.91), 7.197 (10.19), 7.217 (6.29), 7.362 (4.96), 7.365 (4.80), 7.382(7.32), 7.385 (6.93), 7.395 (4.03), 7.411 (2.04), 7.433 (0.82), 7.493(7.91), 7.514 (5.84), 7.667 (8.70), 9.794 (12.87).

Intermediate 764-bromo-N-(2-chloro-6-fluorophenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

4-bromo-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoic Acid (Intermediate 66,1.16 g, 3.80 mmol) was suspended in DCM (5 mL).1-Chlor-1-dimethylamino-2-methyl-1-propen (1.5 ml, 11 mmol) was addedand the mixture was stirred at room temperature for 30 minutes. Pyridine(1.5 ml, 19 mmol) and 2-chloro-6-fluoroaniline (830 mg, 5.70 mmol) wasadded as a solution in DCM (5 mL). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was concentrated and purifiedusing column chromatography (hexanes/ethyl acetate: 0-70%) to yield 1.31g (98% purity, 78% yield) of desired product.

LC-MS (Method A): R_(t)=1.61 min; MS (ESIneg): m/z=430 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.863 (7.04), 0.882 (16.00), 0.900(8.01), 1.291 (9.46), 1.307 (9.57), 1.345 (1.10), 1.369 (1.27), 1.386(1.19), 1.402 (1.14), 1.420 (1.08), 1.437 (1.19), 1.455 (1.10), 1.472(0.67), 1.488 (0.41), 1.542 (0.54), 1.556 (0.95), 1.578 (1.10), 1.590(1.38), 1.602 (1.06), 1.614 (0.97), 1.629 (0.48), 1.720 (0.60), 1.736(0.97), 1.752 (1.10), 1.795 (0.63), 2.327 (0.93), 2.669 (0.97), 4.724(0.99), 4.738 (1.73), 4.753 (1.71), 4.767 (0.93), 7.327 (1.06), 7.348(2.53), 7.372 (1.84), 7.379 (1.34), 7.399 (2.18), 7.413 (2.33), 7.433(4.92), 7.454 (1.49), 7.631 (4.99), 7.640 (3.63), 7.653 (3.41), 9.784(4.77).

Intermediate 774-bromo-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Intermediate 76 from Intermediate 66 and2-methoxy-4-methylpyridin-3-amine.

LC-MS (Method A): R_(t)=1.56 min; MS (ESIneg): m/z=423 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.876 (3.55), 0.894 (7.83), 0.913(3.92), 1.172 (0.61), 1.298 (7.01), 1.313 (7.15), 1.363 (0.58), 1.387(0.78), 1.405 (0.87), 1.422 (0.91), 1.445 (0.73), 1.464 (0.64), 1.483(0.45), 1.578 (0.53), 1.597 (0.64), 1.612 (0.86), 1.621 (0.62), 1.636(0.62), 1.722 (0.65), 1.737 (0.65), 1.746 (0.66), 1.988 (1.14), 2.188(13.60), 2.327 (0.81), 2.669 (0.77), 3.867 (16.00), 4.757 (0.62), 4.773(1.19), 4.788 (1.18), 4.803 (0.61), 6.935 (2.45), 6.948 (2.45), 7.628(2.37), 7.642 (2.38), 7.660 (2.73), 7.683 (2.67), 7.960 (2.69), 7.973(2.58), 9.587 (2.92).

Intermediate 784-bromo-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Intermediate 76 from Intermediate 66 and2-fluoro-6-methylaniline

LC-MS (Method A): R_(t)=1.60 min; MS (ESIpos): m/z=412 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.863 (4.41), 0.882 (9.67), 0.900(4.96), 1.154 (0.51), 1.172 (1.00), 1.190 (0.52), 1.276 (8.57), 1.291(8.62), 1.322 (0.59), 1.331 (0.67), 1.340 (0.78), 1.358 (0.83), 1.365(0.92), 1.372 (0.79), 1.382 (0.96), 1.398 (0.92), 1.414 (0.84), 1.427(0.92), 1.446 (0.87), 1.464 (0.48), 1.526 (0.42), 1.539 (0.71), 1.559(0.80), 1.574 (1.06), 1.584 (0.78), 1.598 (0.77), 1.681 (0.50), 1.696(0.77), 1.711 (0.82), 1.721 (0.80), 1.755 (0.47), 1.988 (1.85), 2.257(16.00), 2.303 (0.44), 4.018 (0.45), 4.035 (0.45), 4.684 (0.76), 4.700(1.44), 4.715 (1.41), 4.729 (0.74), 7.098 (1.05), 7.119 (3.75), 7.136(3.06), 7.224 (1.05), 7.238 (1.32), 7.243 (1.63), 7.257 (1.32), 7.277(0.61), 7.583 (5.97), 7.599 (3.30), 7.605 (3.58), 9.600 (3.47).

Intermediate 794-bromo-5-fluoro-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Intermediate 76 from Intermediate 66 andpentan-3-amine.

LC-MS (Method A): R_(t)=1.62 min; MS (ESIneg): m/z=372 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.849 (6.80), 0.868 (16.00), 0.889(13.47), 0.908 (4.47), 1.236 (7.73), 1.251 (7.64), 1.354 (1.75), 1.372(2.45), 1.391 (2.90), 1.410 (2.75), 1.429 (1.79), 1.494 (0.58), 1.512(1.53), 1.526 (2.19), 1.544 (2.51), 1.559 (2.27), 1.571 (1.81), 1.596(1.55), 1.612 (1.25), 1.626 (0.97), 1.638 (0.97), 3.761 (1.08), 3.780(1.28), 4.681 (0.79), 4.696 (1.44), 4.711 (1.42), 4.726 (0.75), 7.524(2.62), 7.538 (2.63), 7.564 (2.68), 7.587 (2.65), 7.851 (1.45), 7.873(1.44).

Intermediate 802,5-difluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzonitrile

4-methyl-5-(propan-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.91 g,20.6 mmol) and potassium carbonate (5.70 g, 41.2 mmol) were suspended inacetonitrile (50 ml). 2,4,5-trifluorobenzonitrile (2.4 ml, 21 mmol) wasadded and the mixture was refluxed overnight. The mixture was cooled andthe precipitate was filtered off. The solids were was washed withacetonitrile and the combined washes were concentrated. The resultingsolid was washed, triturated with hexanes, and filtered. The solids werewashed with hexanes and dried to yield the desired product (5.3 g, 91%yield).

Intermediate 815-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzonitrile

Sodium hydride (115 mg, 60% purity, 2.87 mmol) was suspended inacetonitrile (10 mL). (2S)-4-methylpentan-2-ol (230 μl, 1.8 mmol) wasadded as a solution in acetonitrile (5 mL). The mixture was stirred atroom temperature for 30 minutes.2,5-difluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzonitrile(Intermediate 80, 400 mg, 1.44 mmol) was added and the mixture wasstirred at room temperature overnight. The reaction was quenched withmethanol (5 mL) and water (2 mL) and concentrated. The resulting residuewas dissolved in ethyl acetate, washed with water (2×), dried, andconcentrated. The crude product was purified using reverse phasepreparative HPLC to yield the desired product (358 mg, 69% yield).

Intermediate 825-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}benzoicAcid

5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}benzonitrile(Intermediate 81, 328 mg, 910 μmol) was dissolved in ethanol (3 mL).Sodium hydroxide solution (−22% in water, 3 mL) was added and themixture was stirred at 90° C. overnight. The mixture was cooled to roomtemperature and concentrated. The residue was diluted with water andextracted with ethyl acetate (3×). The aqueous layer was acidified to pH3 using 1N hydrochloric acid. The aqueous phase was extracted with ethylacetate (3×) and the combined organic fractions were dried andconcentrated. Preparative reverse phase chromatography yield the desiredproduct (262 mg, 75% yield).

Intermediate 83 2,4,5-trifluoro-N-(2-methylphenyl)benzamide

2,4,5-trifluorobenzoic acid (6.00 g, 34.1 mmol) and 2-methylaniline(5.48 g, 51.1 mmol) were dissolved in dichloromethane (100 ml).Triethylamine (6.88 g, 68.1 mmol) and HATU (19.4 g, 51.1 mmol) wereadded. The mixture was stirred at room temperature for 1 h. The reactionmixture was washed with aqueous hydrochloric acid (1N), saturated sodiumcarbonate solution, and brine. The organic layer was dried andconcentrated to yield 7.6 g of the desired product (84% yield).

Intermediate 84 2,4,5-trifluoro-N-(pentan-3-yl)benzamide

Synthesized analogously to Intermediate 83 using 2,4,5-trifluorobenzoicacid and pentan-3-amine.

Intermediate 854-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluoro-N-(pentan-3-yl)benzamide

2,4,5-trifluoro-N-(pentan-3-yl)benzamide (Intermediate 84, 1.00 g, 4.08mmol) and5-[1-(1-ethoxyethoxy)ethyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 4, 1.00 g, 4.65 mmol) were dissolved in acetonitrile (20mL). Potassium carbonate (1.00 g, 7.24 mmol) was added and the mixturewas stirred at 80° C. overnight. The mixture was concentrated, suspendedin water and extracted with ethyl acetate. The organic layer was driedand concentrated. The crude product was purified using columnchromatography to yield the desired product (300 mg, 16% yield).

Intermediate 864-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2,5-difluoro-N-(2-methylphenyl)benzamide

Synthesized analogously to Intermediate 83 using and Intermediate 4.

Intermediate 874-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluoro-N-(pentan-3-yl)benzamide

Synthesized analogously to Intermediate 85 using Intermediate 84 and3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

Intermediate 884-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzonitrile

5-ethyl-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (3.00 g, 23.6 mmol)and potassium carbonate (6.52 g, 47.2 mmol) were suspended inacetonitrile (50 ml). The mixture was stirred at reflux overnight. Themixture was filtered and the filter cake was washed with acetonitrile.The solvent was concentrated and the residue was triturated with hexanesto yield the desired intermediate.

LC-MS (Method A): R_(t)=0.93 min; MS (ESIpos): m/z=265 [M+H]⁺

Intermediate 89 4-bromo-2-{[1,1-difluoropropan-2-yl]oxy}benzonitrile(Racemic)

Synthesized analogously to Intermediate 62 from4-bromo-2-fluorobenzonitrile and 1,1-difluoropropan-2-ol.

LC-MS (Method A): R_(t)=1.23 min; MS (ESIpos): m/z=276 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.331 (16.00), 1.344 (9.60), 1.347(15.75), 2.518 (2.46), 2.522 (1.72), 2.673 (0.49), 3.350 (3.94), 3.380(4.43), 3.387 (1.48), 3.401 (1.35), 3.404 (1.72), 3.409 (0.49), 3.414(0.49), 3.416 (0.49), 5.072 (0.74), 5.080 (0.86), 5.088 (0.86), 5.096(0.98), 5.100 (1.48), 5.108 (1.60), 5.116 (1.48), 5.124 (1.60), 5.136(0.86), 5.144 (0.74), 5.152 (0.62), 6.108 (2.58), 6.115 (2.46), 6.245(4.80), 6.252 (4.92), 6.381 (2.22), 6.389 (2.34), 7.362 (8.25), 7.366(7.51), 7.383 (8.12), 7.386 (8.86), 7.707 (15.14), 7.727 (13.54), 7.740(9.60), 7.744 (9.48).

Intermediate 904-bromo-2-{[3,3-difluorobutan-2-yl]oxy}-5-fluorobenzonitrile (Racemic)

Synthesized analogously to Intermediate 62 from4-bromo-2,5-difluorobenzonitrile and 3,3-difluorobutan-2-ol

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.343 (12.26), 1.359 (12.22), 1.665(8.25), 1.692 (0.75), 1.714 (16.00), 1.763 (7.25), 2.518 (1.70), 2.522(1.10), 2.727 (2.33), 2.888 (2.89), 3.318 (0.56), 3.347 (0.56), 5.009(0.92), 5.016 (0.51), 5.025 (1.05), 5.031 (1.32), 5.040 (0.76), 5.047(1.30), 5.055 (1.04), 5.062 (0.52), 5.071 (0.91), 5.756 (1.06), 7.896(6.28), 7.910 (6.32), 7.972 (9.05), 7.993 (8.72), 8.149 (0.67), 8.162(0.72), 8.166 (0.75), 8.170 (0.72), 8.179 (0.72), 8.184 (0.83), 8.186(0.81), 8.200 (0.68).

Intermediate 914-bromo-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzonitrile

Synthesized analogously to Intermediate 62 from4-bromo-2,3-difluorobenzonitrile and (S)-1,1,1-trifluoropropanol.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.378 (1.16), 1.395 (1.13), 1.437(1.13), 1.453 (1.16), 1.525 (15.67), 1.541 (16.00), 2.518 (1.82), 2.523(1.27), 2.728 (4.04), 2.888 (4.76), 5.172 (1.31), 5.189 (3.21), 5.205(4.23), 5.221 (3.08), 5.236 (1.19), 7.656 (4.97), 7.661 (5.29), 7.678(9.93), 7.682 (11.32), 7.719 (9.88), 7.734 (9.24), 7.741 (5.13), 7.756(4.79), 7.763 (0.86), 7.950 (0.58).

Intermediate 922-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzonitrile

To a solution of (2S)-1-(dimethylamino)propan-2-ol (234 mg, 2.27 mmol)in THF (16 ml, 200 mmol), cooled to 0° C., was slowly added sodiumhydride (90.8 mg, 60% in mineral oil, 2.27 mmol).4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluorobenzonitrile(Intermediate 88, 500 mg, 1.89 mmol) was added as a solution in THF (3mL). The mixture was stirred at 0° C. for 30 min, and was warmed to roomtemperature overnight. The reaction was quenched with brine and themixture was extracted with ethyl acetate. The organic phase was driedover sodium sulfate, filtered, and concentrated to yield the desiredintermediate (600 mg, 91% yield).

LC-MS (Method A): R_(t)=0.63 min, MS (ESIpos): m/z=349 [M+H]⁺

Intermediate 932-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzoicAcid

To a solution of2-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzonitrile(Intermediate 92, 600 mg, 1.73 mmol) in ethanol (20 ml) was addedaqueous sodium hydroxide (2 N, 20 ml) and the resulting mixture washeated to 90° C. for 2 hours. The resulting solution was cooled to roomtemperature and diluted with water. The aqueous phase was washed withethyl acetate, acidified with hydrochloric acid (1N) and washed withdichloromethane. The aqueous phase was concentrated and the residue waspurified using prepHPLC to yield the desired intermediate (230 mg, 36%yield)

LC-MS (Method A): R_(t)=0.60 min; MS (ESIpos): m/z=367 [M+H]⁺

Intermediate 94 4-bromo-2-{[1,1-difluoropropan-2-yl]oxy}benzoic Acid(Racemic)

Synthesized analogously to Intermediate 65 from Intermediate 89.

LC-MS (Method A): R_(t)=1.09 min; MS (ESIpos): m/z=295 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.281 (15.80), 1.297 (16.00), 2.518(2.76), 2.523 (1.90), 4.864 (0.72), 4.873 (0.92), 4.880 (0.96), 4.892(1.38), 4.901 (1.40), 4.909 (1.37), 4.918 (1.44), 4.928 (0.93), 4.936(0.86), 4.944 (0.67), 6.017 (2.51), 6.026 (2.42), 6.155 (3.98), 6.163(3.96), 6.292 (2.14), 6.300 (2.21), 7.252 (7.16), 7.256 (7.23), 7.272(7.63), 7.277 (7.92), 7.517 (10.22), 7.521 (9.92), 7.559 (15.54), 7.580(13.27).

Intermediate 95 4-bromo-2-{[3,3-difluorobutan-2-yl]oxy}-5-fluorobenzoicAcid (Racemic)

Synthesized analogously to Intermediate 65 from Intermediate 90.

LC-MS (Method A): R_(t)=1.16 min; MS (ESIpos): m/z=327 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.282 (13.39), 1.298 (13.29), 1.346(0.58), 1.362 (0.57), 1.644 (0.63), 1.654 (8.31), 1.693 (1.28), 1.703(16.00), 1.751 (7.31), 2.518 (2.11), 2.522 (1.44), 4.847 (0.98), 4.854(0.65), 4.863 (1.13), 4.870 (1.87), 4.878 (0.76), 4.886 (1.91), 4.893(1.06), 4.901 (0.70), 4.908 (0.93), 7.587 (10.62), 7.610 (9.76), 7.670(6.89), 7.684 (7.00), 7.751 (0.69), 7.766 (0.70), 7.772 (0.68), 7.788(0.66), 7.866 (0.68), 7.880 (0.68), 7.890 (0.69), 7.904 (0.66).

Intermediate 964-bromo-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoic Acid

Synthesized analogously to Intermediate 65 from Intermediate 91.

LC-MS (Method A): R_(t)=1.20 min; MS (ESIneg): m/z=329 [M−H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.303 (0.76), 1.343 (1.08), 1.353(1.37), 1.360 (1.30), 1.368 (1.19), 1.443 (15.98), 1.458 (16.00), 2.518(2.59), 2.523 (1.81), 4.910 (1.21), 4.926 (3.04), 4.942 (3.93), 4.958(2.92), 4.974 (1.23), 5.758 (1.44), 7.535 (4.20), 7.539 (4.02), 7.557(8.36), 7.561 (10.33), 7.584 (8.25), 7.588 (1.84), 7.599 (7.64), 7.605(3.10), 7.609 (0.89), 7.620 (3.90), 13.488 (0.63).

Intermediate 97 4-bromo-2-{[1,1-difluoropropan-2-yl]oxy}benzoyl Chloride(Racemic)

Synthesized analogously to Intermediate 68 from Intermediate 94.

LC-MS (Method A) [methyl ester]: MS (ESIpos): m/z=308 [M+H]⁺.

Intermediate 98 4-bromo-2-{[3,3-difluorobutan-2-yl]oxy}-5-fluorobenzoylChloride (Racemic)

Synthesized analogously to Intermediate 68 from Intermediate 95.

LC-MS (Method A) [methyl ester]: MS (ESIpos): m/z=340 [M+H]⁺.

Intermediate 994-bromo-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoylChloride

Synthesized analogously to Intermediate 68 from Intermediate 96.

LC-MS (Method A) [methyl ester]: MS (ESIpos): m/z=344 [M+H]⁺.

Intermediate 1004-bromo-N-(2-chloro-6-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 69 and2-chloro-6-fluoroaniline

LC-MS (Method A): R_(t)=1.41 min; MS (ESIpos): m/z=440 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.448 (6.01), 1.464 (6.02), 2.085(16.00), 2.518 (1.99), 2.523 (1.32), 5.477 (0.92), 5.492 (1.19), 5.509(0.89), 5.758 (5.07), 7.320 (0.62), 7.340 (1.42), 7.357 (0.90), 7.364(1.25), 7.374 (2.05), 7.394 (3.12), 7.408 (1.65), 7.419 (2.92), 7.425(3.65), 7.440 (0.76), 7.504 (2.49), 7.524 (1.85), 7.674 (2.93), 9.864(4.29).

Intermediate 1014-bromo-N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}benzamide(Racemic)

Synthesized analogously to Intermediate 70 from Intermediate 97 and2-chloro-6-fluoroaniline.

LC-MS (Method A): R_(t)=1.37 min; MS (ESIpos): m/z=422 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.363 (16.00), 1.378 (16.00), 2.518(7.70), 2.523 (5.05), 3.300 (0.84), 3.377 (0.60), 5.075 (1.92), 5.085(1.86), 5.091 (1.86), 5.101 (1.92), 5.758 (1.50), 6.127 (1.92), 6.136(1.86), 6.265 (3.61), 6.273 (3.67), 6.403 (1.80), 6.411 (1.80), 7.319(1.86), 7.323 (2.17), 7.342 (9.50), 7.362 (7.76), 7.367 (9.08), 7.378(2.59), 7.392 (2.11), 7.398 (4.63), 7.411 (4.93), 7.418 (4.03), 7.427(9.26), 7.432 (10.89), 7.447 (2.59), 7.452 (2.05), 7.632 (12.15), 7.653(7.34), 9.699 (11.49).

Intermediate 1024-bromo-N-(2-chloro-6-fluorophenyl)-2-{[3,3-difluorobutan-2-yl]oxy}-5-fluorobenzamide(Racemic)

Synthesized analogously to Intermediate 70 from Intermediate 98 and2-chloro-6-fluoroaniline.

LC-MS (Method A): R_(t)=1.42 min; MS (ESIpos): m/z=454 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (4.72), 1.172 (9.81), 1.190(4.75), 1.237 (1.07), 1.332 (12.43), 1.347 (12.37), 1.383 (0.42), 1.642(8.41), 1.691 (16.00), 1.712 (0.70), 1.739 (7.28), 1.987 (15.86), 2.084(11.61), 2.518 (7.06), 2.522 (4.84), 4.000 (1.15), 4.017 (3.46), 4.035(3.49), 4.053 (1.15), 4.988 (0.84), 5.011 (1.60), 5.028 (1.60), 5.050(0.76), 7.327 (1.21), 7.331 (1.32), 7.347 (2.53), 7.350 (3.15), 7.357(1.57), 7.367 (1.91), 7.374 (2.36), 7.383 (1.55), 7.397 (1.29), 7.403(2.98), 7.417 (3.37), 7.423 (3.04), 7.429 (6.16), 7.435 (8.69), 7.449(1.74), 7.455 (1.27), 7.543 (5.01), 7.564 (5.06), 7.763 (4.44), 7.777(4.44), 9.933 (5.48).

Intermediate 1034-bromo-N-(2-chloro-6-fluorophenyl)-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Intermediate 70 from Intermediate 99 and2-chloro-6-fluoroaniline.

LC-MS (Method A): R_(t)=1.43 min; MS (ESIpos): m/z=458 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.053 (0.80), 1.330 (0.50), 1.348(0.50), 1.363 (0.57), 1.378 (0.46), 1.418 (15.92), 1.434 (16.00), 2.518(4.32), 2.523 (3.05), 4.945 (1.22), 4.961 (2.98), 4.977 (3.86), 4.993(2.79), 5.010 (1.07), 7.345 (5.00), 7.348 (4.93), 7.365 (7.33), 7.369(7.98), 7.376 (2.18), 7.385 (2.29), 7.393 (3.02), 7.400 (1.87), 7.414(1.37), 7.421 (3.63), 7.434 (4.35), 7.443 (8.10), 7.450 (8.78), 7.464(1.83), 7.469 (1.03), 7.660 (3.78), 7.675 (4.09), 7.681 (3.63), 7.696(3.32), 10.345 (6.42).

Intermediate 1042-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzoicAcid

Synthesized analogously to Intermediate 39 from Intermediate 15 and(1S)-1-cyclohexylethanol

LC-MS (Method A): R_(t)=1.25 min, MS (ESIpos): m/z=392 [M+H]⁺

Experimental Section—Examples Example 15-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

To a 0° C. stirred solution of5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicacid (Intermediate 39, 98.0 mg, 0.25 mmol, 1.00 eq.) and catalytic DMFin anhydrous DCM (0.65 mL, 0.40 mol/L) was added oxalyl chloride (34.9mg, 0.28 mmol, 1.10 eq.) dropwise. The resulting mixture was warmed toroom temperature, stirred for 1 h and concentrated under reducedpressure. A solution of the residue in anhydrous DCM (0.83 mL, 0.30mol/L) was added dropwise to a 0° C. stirred solution of o-toluidine(29.5 mg, 0.28 mmol, 1.10 eq.) and triethylamine (27.8 mg, 0.28 mmol,1.10 eq.) in anhydrous DCM (0.92 mL, 0.30 mol/L). Following completeaddition, the mixture was warmed to room temperature and stirred for 1h. Aqueous 1.0 M hydrochloric acid was added to the mixture andextracted with DCM (3×). The combined organic extracts were washed withbrine, dried (magnesium sulfate) and concentrated under reducedpressure. The residue was purified by flash column chromatography(hexanes/ethyl acetate) to give the desired product (103 mg, 86%).

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.62 (d, 3H), 2.31 (s,3H), 2.38 (s, 3H), 4.34 (sep, 1H), 4.83-4.98 (q, 1H), 7.13 (t, 1H),7.21-7.30 (m, 2H), 7.46 (d, 1H), 7.89 (d, 1H), 8.14 (d, 1H), 9.03 (s,1H).

MS (ESIpos): m/z=481 (M+H)⁺.

Example 2N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogous to Example 1 from Intermediate 39 and2,6-difluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.64 (d, 3H), 2.38 (s,3H), 4.34 (sep, 1H), 4.85-4.99 (m, 1H), 6.94-7.05 (m, 2H), 7.19-7.30 (m,1H), 7.49 (d, 1H), 8.15 (d, 1H), 8.98 (s, 1H).

MS (ESIpos): m/z=503 (M+H)⁺.

Example 35-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogous to Example 1 from Intermediate 39 and2-fluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.66 (d, 3H), 2.38 (s,3H), 4.34 (sep, 1H), 4.86-5.01 (m, 1H), 7.04-7.23 (m, 3H), 7.48 (d, 1H),8.16 (d, 1H), 8.54 (td, 1H), 9.77 (s, 1H).

MS (ESIpos): m/z=485 (M+H)⁺.

Example 45-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenyl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogous to Example 1 from Intermediate 39 and3-(trifluoromethyl)aniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.66 (d, 3H), 2.38 (s,3H), 4.33 (sep, 1H), 4.88-5.01 (m, 1H), 7.40 (d, 1H), 7.45-7.52 (m, 2H),7.79 (d, 1H), 8.04 (s, 1H), 8.17 (d, 1H), 9.62 (s, 1H).

MS (ESIpos): m/z=535 (M+H)⁺.

Example 55-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogous to Example 1 from Intermediate 39 and2-fluoro-6-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.56 (d, 6H), 1.64 (d, 3H), 2.30 (s,3H), 2.38 (s, 3H), 4.34 (sep, 1H), 4.87-5.00 (m, 1H), 6.96-7.09 (m, 2H),7.19 (dd, 1H), 7.47 (d, 1H), 8.15 (d, 1H), 8.87 (s, 1H).

MS (ESIpos): m/z=499 (M+H)⁺.

Example 65-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogous to Example 1 from Intermediate 41 and2-fluoroaniline

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.52 (d, 6H), 1.84 (d, 3H), 2.32 (s,3H), 4.30 (sep, 1H), 5.61 (q, 1H), 7.04-7.44 (m, 9H), 8.11 (d, 1H) 8.64(d, 1H), 10.5 (s, 1H).

MS (ESIpos): m/z=493 (M+H)⁺.

Example 75-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogous to Example 1 from Intermediate 41 and2-fluoro-6-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.53 (d, 6H), 1.78 (d, 3H), 2.29 (s,3H), 2.33 (s, 3H), 4.32 (sep, 1H), 5.61 (q, 1H), 6.97-7.08 (m, 2H),7.13-7.22 (m, 1H), 7.28-7.45 (m, 6H), 8.10 (d, 1H), 9.59 (s, 1H).

MS (ESIneg): m/z=505 (M−H)⁻.

Example 8N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogous to Example 1 from Intermediate 41 and2,6-difluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.53 (d, 6H), 1.80 (d, 3H), 2.33 (s,3H), 4.31 (sep, 1H), 5.61 (q, 1H), 6.96-7.05 (m, 2H), 7.17-7.46 (m, 7H),8.10 (d, 1H) 9.72 (s, 1H).

MS (ESIpos): m/z=511 (M+H)⁺.

Example 95-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]-N-[3-(trifluoromethyl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 41 and3-(trifluoromethyl)aniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.55 (d, 6H), 1.86 (s, 3H), 2.36 (s,3H), 4.33 (sep, 1H), 5.61 (q, 1H), 7.32-7.49 (m, 8H), 7.64 (s, 1H), 7.76(d, 1H), 8.12 (d, 1H), 10.2 (s, 1H).

MS (ESIneg): m/z=541 (M−H)⁻.

Example 105-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methyl-phenyl)-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogous to Example 1 from Intermediate 41 and2-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.53 (d, 6H), 1.79 (d, 3H), 2.18 (s,3H), 2.34 (s, 3H), 4.32 (sep, 1H), 5.62 (q, 1H), 7.06-7.42 (m, 9H), 8.02(d, 1H) 8.14 (d, 1H), 9.64 (s, 1H).

MS (ESIpos): m/z=489 (M+H)⁺.

Example 115-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 42 and2-fluoro-6-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.95 (t, 3H), 1.38-1.54 (m, 2H), 1.43(d, 3H), 1.56 (d, 6H), 1.62-1.76 (m, 1H), 1.77-1.91 (m, 1H), 2.32 (s,3H), 2.38 (s, 3H), 4.35 (sep, 1H), 4.61-4.71 (m, 1H), 6.95-7.09 (m, 2H),7.17 (dd, 1H), 7.39 (d, 1H), 8.13 (d, 1H), 9.56 (s, 1H).

MS (ESIpos): m/z=473 (M+H)⁺.

Example 12N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 42 and2,6-difluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.96 (t, 3H), 1.38-1.55 (m, 2H), 1.43(d, 3H), 1.56 (d, 6H), 1.62-1.77 (m, 1H), 1.79-1.93 (m, 1H), 2.37 (s,3H), 4.35 (sep, 1H), 4.60-4.73 (m, 1H), 6.95-7.04 (m, 2H), 7.16-7.29 (m,1H), 7.40 (d, 1H), 8.13 (d, 1H), 9.69 (s, 1H).

MS (ESIpos): m/z=477 (M+H)⁺.

Example 135-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methyl-phenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 42 and2-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.94 (t, 3H), 1.37-1.53 (m, 2H), 1.42(d, 3H), 1.56 (d, 6H), 1.60-1.74 (m, 1H), 1.77-1.93 (m, 1H), 2.34 (s,3H), 2.37 (s, 3H), 4.35 (sep, 1H), 4.59-4.72 (m, 1H), 7.11 (t, 1H),7.19-7.30 (m, 2H), 7.39 (d, 1H), 8.01 (d, 1H), 8.16 (d, 1H), 9.66 (s1H).

MS (ESIpos): m/z=455 (M+H)⁺.

Example 145-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 42 and3-(trifluoromethyl)aniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 1.00 (t, 3H), 1.41-1.61 (m, 2H), 1.47(d, 3H), 1.55 (d, 6H), 1.70-1.98 (m, 2H), 2.37 (s, 3H), 4.34 (sep, 1H),4.61-4.74 (m, 1H), 7.35-7.41 (m, 2H), 7.48 (t, 1H), 7.84 (d, 1H), 7.94(s, 1H), 8.13 (d, 1H), 10.4 (s, 1H).

MS (ESIpos): m/z=509 (M+H)⁺.

Example 155-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 42 and2-fluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.96 (t, 3H), 1.35-1.53 (m, 2H), 1.44(d, 3H), 1.56 (d, 6H), 1.63-1.79 (m, 1H), 1.86-2.01 (m, 1H), 2.37 (s,3H), 4.35 (sep, 1H), 4.61-4.73 (m, 1H), 7.01-7.22 (m, 3H), 7.38 (d, 1H),8.16 (d, 1H), 8.62 (td, 1H), 10.5 (s, 1H).

MS (ESIpos): m/z=457 (M+H)⁺.

Example 164-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.94 (t, 3H), 1.36 (t, 3H), 1.40-1.54(m, 2H), 1.43 (d, 3H), 1.60-1.74 (m, 1H), 1.79-1.89 (m, 1H), 2.34 (s,3H), 2.65 (q, 2H), 3.33 (s, 3H), 4.59-4.70 (m, 1H), 7.11 (td, 1H),7.20-7.30 (m, 2H), 7.36 (d, 1H), 8.02 (d, 1H), 8.17 (d, 1H), 9.65 (s,1H).

MS (ESIpos): m/z=441 (M+H)⁺.

Example 174-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-fluoro-6-methylaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.95 (t, 3H), 1.36 (t, 3H), 1.43 (d,3H), 1.43-1.58 (m, 2H), 1.62-1.75 (m, 1H), 1.77-1.92 (m, 1H), 2.31 (s,3H), 2.65 (q, 2H), 3.33 (s, 3H), 4.59-4.71 (m, 1H), 6.95-7.09 (m, 2H),7.17 (dd, 1H), 7.36 (d, 1H), 8.13 (d, 1H), 9.55 (s, 1H).

MS (ESIpos): m/z=459 (M+H)⁺.

Example 18N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2,6-difluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.92 (t, 3H), 1.36 (t, 3H), 1.38-1.59(m, 2H), 1.43 (d, 3H), 1.63-1.77 (m, 1H), 1.79-1.93 (m, 1H), 2.65 (q,2H), 3.32 (s, 3H), 4.59-4.71 (m, 1H), 6.94-7.05 (m, 2H), 7.16-7.25 (m,1H), 7.37 (d, 1H), 8.13 (d, 1H), 9.68 (s, 1H).

MS (ESIpos): m/z=463 (M+H)⁺.

Example 194-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-fluoroaniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.96 (t, 3H), 1.36 (t, 3H), 1.38-1.59(m, 2H), 1.45 (d, 3H), 1.64-1.78 (m, 1H), 1.86-2.01 (m, 1H), 2.65 (q,2H), 3.33 (s, 3H), 4.59-4.72 (m, 1H), 7.02-7.22 (m, 3H), 7.35 (d, 1H),8.16 (d, 1H), 8.62 (td, 1H), 10.5 (s, 1H).

MS (ESIpos): m/z=445 (M+H)⁺.

Example 204-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and3-(trifluoromethyl)aniline.

¹H NMR (300 MHz, CDCl₃) δ [ppm] 0.99 (t, 3H), 1.36 (t, 3H), 1.40-1.64(m, 2H), 1.47 (d, 3H), 1.70-1.99 (m, 2H), 2.65 (q, 2H), 3.33 (s, 3H),4.60-4.72 (m, 1H), 7.34-7.41 (m, 2H), 7.49 (t, 1H), 7.85 (d, 1H), 7.93(s, 1H), 8.14 (d, 1H), 10.3 (s, 1H).

MS (ESIpos): m/z=495 (M+H)⁺.

Example 214-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and4-methoxyaniline.

Example 224-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(trifluoromethyl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and4-(trifluoromethyl)aniline.

Example 234-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(trifluoromethyl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-(trifluoromethyl)aniline.

Example 24N-(3-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-methylbenzene-1,3-diamine.

Example 25N-(2-cyano-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-amino-3-methylbenzonitrile.

Example 264-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and m-toluidine.

Example 27N-(2,2-dimethylpropyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2,2-dimethylpropan-1-amine.

Example 28N-cycloheptyl-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 andcycloheptanamine.

Example 294-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-hydroxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-aminophenol.

Example 30N-(cyclohexylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and1-cyclohexylmethanamine.

Example 31N-(1-cyclohexylethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 1 from Intermediate 44 and1-cyclohexylethanamine.

Example 32N-(2,4-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2,4-dimethylaniline.

Example 334-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[2-(methylamino)-phenyl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 andN-methylbenzene-1,2-diamine.

Example 344-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-methoxyaniline.

Example 354-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and3-methoxyaniline.

Example 364-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-ethylaniline.

Example 374-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(propan-2-yl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-isopropylaniline.

Example 384-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-(2-propylphenyl)benzamide

Synthesized analogous to Example 1 from Intermediate 44 and2-propylaniline.

Example 394-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and4-ethylaniline.

Example 404-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(propan-2-yl)phenyl]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and4-isopropylaniline.

Example 41N-(2,3-dihydro-1H-inden-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 andindan-2-amine.

Example 42N-(cyclopentylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and1-cyclopentylmethanamine.

Example 434-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogous to Example 1 from Intermediate 44 and p-toluidine.

Example 44N-(4-amino-2,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamideStep Atert-butyl[4-({4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzoyl}amino)-3,5-dimethylphenyl]carbamate

Synthesized analogous to Example 1 from Intermediate 44 and tert-butyl(4-amino-3,5-dimethylphenyl)carbamate.

Step BN-(4-amino-2,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

The intermediate from STEP A was dissolved in methanol and hydrogenchloride gas was bubbled through the reaction for 20 minutes. Thesolvent was evaporated to yield pure product.

Example 45N-(2-amino-4,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamideStep AN-(2,4-dimethyl-6-nitrophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-benzoicacid (Intermediate 44, 100 mg, 285 μmol) and 2,4-dimethyl-6-nitroaniline(47.0 mg, 283 μmol) were dissolved in THF (10 mL) and pyridine (1 mL).Phosphoryl chloride (500 μl, 5.4 mmol) was added and the mixture wasstirred overnight. The reaction mixture was concentrated and the crudeproduct was purified using preparative TLC to yield the desiredintermediate (70 mg, 49% yield).

Step BN-(2-amino-4,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

N-(2,4-dimethyl-6-nitrophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide(Intermediate from STEP A, 70.0 mg, 140 μmol) was dissolved in methanol(20 mL). Raney-Nickel (10 mg) was added and the mixture was stirredunder an atmosphere of hydrogen overnight. The reaction mixture wasfiltered and concentrated and the crude product was purified usingpreparative TLC to yield the desired intermediate (22 mg, 33% yield).

Example 46N-[4-(aminomethyl)-3-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pentan-2-yloxy)benzamideStep AN-(4-cyano-3-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 45 (STEP A) from Intermediate 44 and4-amino-3-methylbenzonitrile.

Step BN-[4-(aminomethyl)-3-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pentan-2-yloxy)benzamide

Synthesized analogously to Example 45 (STEP B) from Intermediate 44.

Example 474-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Step A

4-(3-Cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-tri-fluoropropan-2-yl]oxy}benzoicacid (Intermediate 54, 699 mg, 1.80 mmol) was dissolved DCM (9 mL). DMF(14 μl, 180 μmol) was added followed by oxalyl chloride (190 μl, 2.2mmol). The mixture was stirred at room temperature for 2 h. The reactionwas concentrated to yield the desired acid chloride (648 mg, 88%) whichwas used directly in the next step.

Step B

4-(3-Cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-tri-fluoropropan-2-yl]oxy}benzoylchloride (Intermediate from STEP A, 143 mg, 351 μmol) was dissolved inDCM (2 mL) and added to a solution of 2,6-difluoroaniline (42 μl, 390μmol) and triethylamine (54 μl, 390 μmol) in DCM (3 mL). The mixture wasstirred at room temperature for 1 h. The reaction was concentrated andpurified using preparative chromatography (water+0.1% formicacid/acetonitrile gradient) to yield the desired product (63.5 mg, 97%purity, 35% yield).

LC-MS (Method A): R_(t)=1.24 min, MS (ESIpos): m/z=501 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.893 (1.75), 0.899 (1.96), 0.906(1.85), 0.911 (1.88), 0.920 (0.81), 0.972 (0.81), 0.981 (1.83), 0.987(1.37), 0.992 (1.24), 1.002 (1.96), 1.007 (1.37), 1.424 (3.81), 1.439(3.78), 1.975 (0.61), 1.983 (0.69), 1.995 (1.17), 2.008 (0.63), 2.327(0.71), 2.518 (3.02), 2.523 (2.03), 2.669 (0.74), 3.324 (16.00), 5.279(0.61), 5.294 (0.81), 7.189 (1.14), 7.210 (2.39), 7.230 (1.50), 7.407(0.81), 7.514 (1.45), 7.529 (1.47), 7.549 (1.63), 7.573 (1.57), 9.963(3.50).

Example 484-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 54 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.28 min; MS (ESIpos): m/z=497 [M+H]⁺.

Example 494-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 54 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.25 min; MS (ESIpos): m/z=483 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.990 (1.13), 0.996 (2.27),0.999 (1.38), 1.002 (1.74), 1.006 (1.83), 1.010 (1.47), 1.015 (5.11),1.018 (2.51), 1.186 (1.84), 1.499 (1.43), 1.581 (3.60), 1.596 (3.60),1.657 (1.14), 3.359 (16.00), 7.030 (0.99), 7.039 (0.79), 7.044 (1.46),7.071 (0.95), 7.341 (1.58), 7.354 (1.57), 8.059 (2.00), 8.088 (2.04),8.465 (0.91), 8.470 (0.98).

Example 504-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 55 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.31 min, MS (ESIpos): m/z=515 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.232 (0.96), 1.434 (4.95), 1.450(4.91), 1.914 (0.75), 2.034 (0.66), 2.055 (1.18), 2.078 (1.01), 2.083(1.01), 2.105 (0.66), 2.280 (0.92), 2.285 (1.05), 2.296 (1.36), 2.304(3.86), 2.317 (2.41), 2.325 (5.35), 2.337 (1.62), 2.346 (1.71), 2.518(5.39), 2.523 (3.55), 2.665 (0.88), 2.669 (1.18), 2.674 (0.83), 3.152(16.00), 3.613 (1.05), 3.634 (1.58), 3.654 (1.01), 5.300 (0.79), 5.317(1.01), 5.332 (0.75), 7.191 (1.40), 7.212 (2.89), 7.232 (1.75), 7.407(0.92), 7.568 (3.51), 7.583 (1.88), 7.592 (2.10), 9.982 (2.72).

Example 514-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 55 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.30 min; MS (ESIpos): m/z=511 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.434 (4.63), 1.450 (4.60), 2.057(0.89), 2.080 (0.80), 2.084 (0.80), 2.273 (11.08), 2.305 (2.80), 2.313(1.22), 2.317 (1.56), 2.326 (4.06), 2.347 (1.13), 2.351 (0.90), 2.518(2.48), 2.522 (1.65), 2.668 (0.69), 3.154 (16.00), 3.611 (0.78), 3.614(0.81), 3.633 (1.19), 3.635 (1.16), 3.654 (0.77), 3.656 (0.75), 5.360(0.96), 7.119 (1.50), 7.124 (1.44), 7.136 (1.64), 7.145 (0.92), 7.228(0.75), 7.242 (0.80), 7.249 (1.05), 7.549 (2.62), 7.563 (2.05), 7.574(3.13), 7.577 (2.32), 9.803 (2.69).

Example 524-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 55 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.37 min; MS (ESIpos): m/z=497 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.478 (4.55), 1.494 (4.51), 2.056(1.02), 2.078 (0.88), 2.083 (0.88), 2.297 (1.08), 2.305 (3.20), 2.313(1.47), 2.318 (1.84), 2.326 (4.39), 2.337 (1.09), 2.347 (1.31), 2.351(1.01), 2.518 (2.20), 2.523 (1.41), 3.154 (16.00), 3.613 (0.88), 3.615(0.91), 3.634 (1.26), 3.636 (1.35), 3.655 (0.85), 3.658 (0.80), 5.432(0.96), 7.211 (0.78), 7.216 (0.97), 7.219 (1.54), 7.223 (1.72), 7.226(1.41), 7.230 (2.19), 7.238 (1.50), 7.244 (1.38), 7.299 (0.79), 7.305(0.71), 7.326 (0.83), 7.617 (1.81), 7.631 (1.76), 7.738 (2.06), 7.765(2.03), 8.083 (1.05), 8.088 (0.87), 10.021 (2.26).

Example 534-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 53 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.30 min; MS (ESIpos): m/z=515 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.897 (1.19), 0.909 (4.05), 0.915(4.68), 0.922 (4.54), 0.927 (4.40), 0.936 (2.17), 0.985 (1.82), 0.994(4.26), 1.000 (3.21), 1.005 (2.93), 1.015 (4.61), 1.021 (3.28), 1.033(1.19), 1.272 (6.85), 1.290 (16.00), 1.308 (7.06), 1.425 (9.15), 1.440(9.15), 2.009 (0.70), 2.022 (1.40), 2.030 (1.61), 2.035 (0.98), 2.042(2.79), 2.050 (1.05), 2.055 (1.47), 2.063 (1.33), 2.332 (1.54), 2.336(0.70), 2.518 (8.31), 2.523 (5.66), 3.800 (1.89), 3.818 (6.01), 3.836(5.94), 3.854 (1.75), 5.295 (1.47), 5.311 (1.89), 5.326 (1.40), 7.190(2.79), 7.210 (5.87), 7.230 (3.63), 7.386 (1.33), 7.407 (1.96), 7.423(0.98), 7.428 (1.05), 7.533 (3.63), 7.546 (6.71), 7.571 (3.84), 9.958(8.87).

Example 544-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 53 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.33 min; MS (ESIpos): m/z=511 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.896 (0.75), 0.908 (2.62), 0.914(2.86), 0.920 (2.62), 0.927 (2.78), 0.935 (1.23), 0.986 (1.11), 0.995(2.60), 1.001 (1.90), 1.006 (1.75), 1.015 (2.78), 1.021 (1.98), 1.033(0.75), 1.275 (4.37), 1.292 (10.11), 1.311 (4.40), 1.424 (6.95), 1.440(6.95), 2.023 (0.90), 2.031 (1.00), 2.043 (1.77), 2.052 (0.64), 2.055(0.95), 2.064 (0.87), 2.266 (16.00), 2.332 (1.11), 2.518 (6.61), 2.523(4.22), 2.673 (1.13), 3.802 (1.16), 3.820 (3.83), 3.838 (3.78), 3.856(1.08), 5.338 (1.08), 5.354 (1.41), 5.369 (1.03), 7.099 (0.87), 7.116(2.32), 7.120 (2.24), 7.132 (2.47), 7.141 (1.41), 7.225 (1.05), 7.240(1.16), 7.245 (1.59), 7.260 (1.18), 7.265 (0.80), 7.279 (0.64), 7.524(3.83), 7.527 (4.78), 7.539 (3.04), 7.551 (3.70), 9.784 (4.09).

Example 554-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 53 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.40 min, MS (ESIpos): m/z=497 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.900 (1.23), 0.912 (4.19), 0.918(4.67), 0.925 (4.36), 0.930 (4.44), 0.939 (1.94), 0.989 (1.86), 0.997(4.24), 1.003 (3.15), 1.009 (2.89), 1.018 (4.58), 1.024 (3.18), 1.036(1.16), 1.274 (7.04), 1.291 (16.00), 1.310 (7.11), 1.470 (9.74), 1.486(9.70), 2.013 (0.75), 2.026 (1.44), 2.033 (1.61), 2.038 (0.94), 2.046(2.82), 2.054 (1.05), 2.059 (1.49), 2.067 (1.32), 2.518 (3.16), 2.523(2.19), 3.803 (1.92), 3.821 (6.23), 3.839 (6.06), 3.858 (1.79), 5.414(1.57), 5.430 (2.03), 5.446 (1.48), 7.202 (1.36), 7.207 (1.61), 7.213(2.02), 7.216 (3.19), 7.219 (3.64), 7.222 (3.01), 7.226 (4.64), 7.237(3.22), 7.240 (3.13), 7.253 (0.84), 7.296 (1.68), 7.302 (1.52), 7.315(1.21), 7.320 (1.52), 7.324 (1.79), 7.331 (1.02), 7.334 (1.02), 7.348(1.03), 7.579 (3.85), 7.594 (3.81), 7.719 (4.45), 7.745 (4.44), 8.059(1.25), 8.065 (1.13), 8.079 (2.23), 8.085 (1.83), 8.093 (1.08), 8.104(1.08), 10.001 (4.27).

Example 564-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 56 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.21 min; MS (ESIpos): m/z=501 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.967 (1.74), 0.972 (3.20), 0.982(3.59), 0.990 (8.16), 1.425 (4.50), 1.442 (4.51), 2.084 (1.22), 2.327(1.22), 2.337 (16.00), 2.518 (2.48), 2.523 (1.66), 2.669 (0.61), 2.894(0.78), 2.909 (1.37), 5.278 (0.73), 5.295 (0.95), 5.758 (1.12), 7.188(1.41), 7.209 (2.92), 7.229 (1.81), 7.406 (0.99), 7.520 (1.75), 7.534(1.78), 7.547 (2.01), 7.573 (1.90), 9.977 (4.24).

Example 574-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 56 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.25 min; MS (ESIpos): m/z=497 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.968 (1.57), 0.974 (3.00), 0.983(3.36), 0.992 (7.39), 1.425 (5.20), 1.441 (5.20), 2.267 (11.89), 2.326(1.03), 2.331 (1.55), 2.338 (16.00), 2.518 (2.46), 2.522 (1.62), 2.910(1.28), 5.322 (0.83), 5.338 (1.08), 5.354 (0.77), 5.758 (0.60), 7.114(1.82), 7.119 (1.72), 7.131 (1.89), 7.141 (1.06), 7.224 (0.79), 7.238(0.87), 7.245 (1.15), 7.259 (0.91), 7.511 (2.15), 7.525 (2.46), 7.530(2.96), 7.554 (2.57), 9.802 (3.10).

Example 584-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 56 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.31 min; MS (ESIpos): m/z=483 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.970 (1.58), 0.975 (3.12), 0.984(3.26), 0.992 (8.02), 1.469 (4.52), 1.484 (4.50), 2.340 (16.00), 2.912(1.27), 5.411 (0.94), 7.215 (1.46), 7.219 (1.71), 7.226 (2.10), 7.234(1.39), 7.236 (1.45), 7.239 (1.50), 7.294 (0.77), 7.322 (0.82), 7.565(1.78), 7.580 (1.76), 7.716 (2.09), 7.743 (2.00), 8.072 (1.01), 8.078(0.85), 10.017 (2.23).

Example 59N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 57 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.33 min; MS (ESIneg): m/z=527 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.439 (7.13), 1.454 (7.49), 2.323(0.63), 2.327 (0.99), 2.332 (0.92), 2.523 (11.15), 2.665 (0.63), 2.669(0.97), 2.673 (0.91), 3.406 (16.00), 5.267 (1.18), 5.283 (1.55), 5.299(1.21), 7.193 (1.99), 7.214 (4.22), 7.234 (2.64), 7.392 (1.08), 7.408(1.49), 7.428 (0.99), 7.637 (2.69), 7.646 (3.96), 7.651 (4.01), 7.670(2.75), 10.084 (3.43).

Example 605-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 57 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.31 min; MS (ESIpos): m/z=525 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.439 (6.82), 1.455 (6.86), 2.278(16.00), 2.518 (2.40), 2.522 (1.70), 3.408 (13.33), 5.292 (0.44), 5.309(1.08), 5.324 (1.43), 5.340 (1.04), 5.356 (0.40), 7.104 (0.87), 7.120(2.02), 7.126 (2.10), 7.137 (2.42), 7.147 (1.33), 7.231 (1.08), 7.245(1.18), 7.250 (1.58), 7.265 (1.19), 7.270 (0.77), 7.284 (0.66), 7.631(3.93), 7.637 (3.04), 7.652 (3.46), 7.655 (4.24), 9.891 (3.85).

Example 615-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 57 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.38 min; MS (ESIpos): m/z=511 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.470 (7.46), 1.486 (7.50), 2.518(2.27), 2.523 (1.68), 3.408 (16.00), 5.331 (0.51), 5.347 (1.22), 5.363(1.60), 5.379 (1.17), 5.395 (0.45), 7.212 (0.98), 7.222 (2.82), 7.229(3.48), 7.237 (2.90), 7.240 (2.38), 7.246 (3.34), 7.258 (0.66), 7.295(1.35), 7.302 (0.93), 7.311 (0.73), 7.314 (0.82), 7.322 (1.40), 7.331(0.86), 7.336 (0.65), 7.340 (0.59), 7.347 (0.77), 7.666 (3.06), 7.681(3.04), 7.784 (3.78), 7.810 (3.74), 8.014 (1.04), 8.019 (0.75), 8.022(0.76), 8.034 (1.54), 8.039 (1.25), 8.048 (0.85), 8.059 (0.94), 10.097(4.20).

Example 624-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 58 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.32 min, MS (ESIpos): m/z=511 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.972 (2.01), 0.978 (3.38), 0.981(2.92), 0.990 (5.04), 0.996 (7.00), 1.005 (1.83), 1.235 (5.68), 1.254(12.83), 1.273 (5.66), 1.428 (7.03), 1.444 (7.04), 2.269 (16.00), 2.518(2.22), 2.523 (1.55), 2.720 (1.66), 2.739 (5.55), 2.757 (5.26), 2.776(1.52), 2.897 (0.91), 2.905 (0.85), 2.912 (1.74), 2.919 (0.84), 2.923(0.89), 2.928 (0.77), 5.319 (1.10), 5.335 (1.44), 5.352 (1.03), 7.100(0.91), 7.116 (2.37), 7.121 (2.25), 7.133 (2.54), 7.143 (1.44), 7.226(1.12), 7.240 (1.21), 7.246 (1.59), 7.261 (1.24), 7.266 (0.78), 7.280(0.66), 7.517 (2.99), 7.533 (6.26), 7.558 (3.68), 9.796 (4.21).

Example 634-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 58 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.29 min; MS (ESIpos): m/z=515 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.971 (3.22), 0.977 (5.28), 0.980(4.55), 0.989 (7.78), 0.995 (10.76), 1.234 (7.62), 1.252 (16.00), 1.271(7.54), 1.429 (8.50), 1.444 (8.34), 2.331 (1.01), 2.518 (6.33), 2.523(4.27), 2.674 (1.01), 2.719 (2.30), 2.737 (7.09), 2.756 (6.85), 2.775(2.06), 2.896 (1.37), 2.903 (1.37), 2.911 (2.42), 2.922 (1.37), 2.926(1.13), 5.275 (1.37), 5.292 (1.77), 5.308 (1.25), 7.191 (2.58), 7.211(5.28), 7.231 (3.26), 7.388 (1.29), 7.408 (1.81), 7.424 (0.97), 7.429(0.93), 7.526 (3.18), 7.541 (3.35), 7.551 (3.67), 7.576 (3.43), 9.972(7.86).

Example 644-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 58 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.39 min; MS (ESIpos): m/z=497 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.973 (2.62), 0.979 (4.41), 0.982(3.76), 0.990 (6.29), 0.997 (9.11), 1.004 (2.36), 1.234 (7.22), 1.253(16.00), 1.271 (7.41), 1.471 (7.47), 1.487 (7.48), 2.518 (3.96), 2.522(2.63), 2.721 (2.14), 2.739 (6.79), 2.758 (6.64), 2.777 (1.93), 2.898(1.17), 2.906 (1.07), 2.913 (2.18), 2.921 (1.07), 2.924 (1.11), 2.928(0.93), 5.391 (1.20), 5.407 (1.57), 5.423 (1.13), 7.202 (1.05), 7.208(1.26), 7.214 (1.64), 7.216 (2.39), 7.220 (2.80), 7.223 (2.29), 7.227(3.61), 7.235 (2.32), 7.238 (2.42), 7.241 (2.42), 7.296 (1.31), 7.302(1.16), 7.315 (0.93), 7.320 (1.20), 7.324 (1.40), 7.334 (0.84), 7.348(0.80), 7.571 (3.00), 7.585 (2.97), 7.721 (3.60), 7.747 (3.51), 8.056(0.98), 8.075 (1.67), 8.082 (1.35), 8.101 (0.84), 10.010 (3.22).

Example 65N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 59 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.24 min; MS (ESIpos): m/z=503 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.251 (15.90), 1.268 (16.00), 1.431(3.86), 1.447 (3.84), 2.518 (1.83), 2.523 (1.32), 3.012 (0.42), 3.030(1.12), 3.047 (1.52), 3.064 (1.09), 3.081 (0.41), 3.274 (14.97), 5.294(0.63), 5.309 (0.81), 5.326 (0.60), 7.192 (1.14), 7.212 (2.41), 7.232(1.51), 7.386 (0.55), 7.407 (0.80), 7.428 (0.42), 7.550 (1.45), 7.564(2.76), 7.588 (1.59), 9.976 (2.43).

Example 665-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihyro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 59 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.26 min; MS (ESIpos): m/z=499 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.252 (15.82), 1.270 (16.00), 1.432(4.75), 1.447 (4.76), 2.273 (11.02), 2.518 (1.09), 2.523 (0.75), 3.014(0.42), 3.031 (1.15), 3.048 (1.53), 3.065 (1.08), 3.276 (15.10), 5.337(0.75), 5.354 (0.97), 5.369 (0.71), 7.103 (0.61), 7.119 (1.55), 7.123(1.52), 7.136 (1.70), 7.145 (0.94), 7.228 (0.73), 7.242 (0.80), 7.249(1.07), 7.263 (0.83), 7.268 (0.52), 7.282 (0.44), 7.545 (4.28), 7.559(2.07), 7.570 (2.55), 9.798 (2.78).

Example 675-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 59 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.34 min; MS (ESIpos): m/z=485 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.251 (15.85), 1.268 (16.00), 1.475(4.00), 1.491 (4.00), 2.518 (1.61), 2.523 (1.16), 3.015 (0.42), 3.032(1.11), 3.050 (1.49), 3.067 (1.08), 3.277 (15.50), 5.408 (0.64), 5.424(0.85), 5.440 (0.61), 7.205 (0.56), 7.211 (0.66), 7.219 (1.31), 7.223(1.47), 7.226 (1.16), 7.230 (1.96), 7.238 (1.31), 7.244 (1.31), 7.299(0.71), 7.304 (0.64), 7.317 (0.47), 7.326 (0.74), 7.333 (0.41), 7.336(0.42), 7.350 (0.43), 7.596 (1.61), 7.611 (1.58), 7.734 (1.91), 7.759(1.90), 8.061 (0.53), 8.066 (0.44), 8.080 (0.92), 8.086 (0.75), 8.092(0.41), 8.105 (0.48), 10.016 (2.07).

Example 684-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methyl-phenyl)-2-[(1S)-1-phenylethoxy]benzamide

Synthesized from Intermediate 43 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.33 min; MS (ESIneg): m/z=492 [M−H]⁻.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.313 (3.69), 1.331 (7.67),1.350 (3.85), 1.591 (1.61), 1.790 (5.27), 1.806 (5.23), 2.309 (9.88),2.583 (1.18), 2.602 (3.74), 2.621 (3.37), 2.639 (1.04), 3.292 (16.00),5.593 (1.08), 5.609 (1.07), 7.024 (0.96), 7.082 (1.17), 7.181 (0.91),7.195 (0.90), 7.285 (2.08), 7.301 (2.64), 7.319 (1.21), 7.345 (1.36),7.360 (1.17), 7.364 (2.82), 7.381 (1.52), 7.385 (0.98), 7.411 (2.32),7.414 (2.60), 7.417 (1.20), 7.431 (1.57), 7.435 (1.03), 8.102 (2.23),8.131 (2.22), 9.620 (1.35).

Example 69N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide

Synthesized from Intermediate 43 and 2,6-difluoroaniline.

LC-MS (Method A): R_(t)=1.30 min, MS (ESIneg): m/z=495 [M−H]⁻.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.312 (3.65), 1.331 (7.68),1.350 (3.81), 1.574 (3.67), 1.803 (4.93), 1.819 (5.08), 2.582 (1.18),2.601 (3.61), 2.620 (3.37), 2.639 (1.01), 3.291 (16.00), 5.590 (1.01),5.606 (1.02), 7.003 (1.23), 7.023 (2.54), 7.043 (1.76), 7.242 (0.98),7.299 (1.89), 7.302 (1.55), 7.313 (1.82), 7.321 (1.16), 7.349 (1.29),7.364 (1.08), 7.368 (2.69), 7.386 (1.44), 7.388 (0.98), 7.417 (2.19),7.419 (2.49), 7.423 (1.19), 7.437 (1.50), 7.441 (1.03), 8.100 (2.02),8.129 (2.01), 9.743 (1.22).

Example 704-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 40 and 2-fluoroaniline.

LC-MS (Method A): R_(t)=1.29 min; MS (ESIpos): m/z=471 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.356 (3.69), 1.375 (7.75),1.394 (3.90), 1.594 (1.02), 1.664 (3.49), 1.679 (3.50), 2.635 (1.21),2.654 (3.71), 2.673 (3.46), 2.692 (1.05), 3.338 (16.00), 7.109 (1.02),7.118 (0.80), 7.122 (1.44), 7.150 (0.92), 7.450 (1.55), 7.464 (1.56),8.155 (2.04), 8.184 (2.00), 8.546 (0.94), 8.550 (0.98).

Example 714-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 40 and 2-fluoro-6-methylaniline.

LC-MS (Method A): R_(t)=1.21 min; MS (ESIpos): m/z=486 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.357 (3.92), 1.376 (8.19),1.394 (4.10), 1.592 (1.03), 1.644 (3.91), 1.660 (4.02), 2.312 (10.10),2.637 (1.28), 2.656 (3.75), 2.675 (3.80), 2.694 (1.13), 3.339 (16.00),4.929 (0.85), 7.011 (0.99), 7.081 (1.18), 7.188 (0.90), 7.202 (0.88),7.434 (1.79), 7.448 (1.77), 8.144 (2.20), 8.172 (2.18), 8.872 (1.20).

Example 724-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-fluoro-2-methyl-phenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized from Intermediate 40 and 4-fluoro-2-methylaniline.

LC-MS (Method A): R_(t)=1.26 min; MS (ESIpos): m/z=486 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.356 (3.86), 1.375 (8.22),1.394 (4.01), 1.625 (4.50), 1.642 (4.35), 2.297 (10.31), 2.637 (1.27),2.656 (3.73), 2.675 (3.77), 2.694 (1.13), 3.339 (16.00), 4.909 (0.90),6.953 (2.09), 6.974 (1.80), 7.428 (1.85), 7.442 (1.83), 8.128 (2.26),8.157 (2.28), 8.962 (1.11).

Example 735-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzoicacid (Intermediate 61, 100 mg, 254 μmol) was dissolved in DMF (1 mL),HATU was added (193 mg, 509 μmol) and the mixture was stirred at roomtemperature for 15 min. 2-methylaniline (54.5 mg, 509 μmol) was added,followed by N,N-diisopropylethylamine (130 μl, 760 μmol). The mixturewas stirred for 2 h at room temperature. The reaction mixture waspurified using reverse phase HPLC (X-Bridge Prep C18 5 μm OBD Solvent:Water (+0.1% NH₃)/ACN Gradient: 5%-95% ACN in 10 min at 30 ml/min) toyield the desired product (48.0 mg (99% purity, 39% yield).

LC-MS (Method A): R_(t)=1.15 min; MS (ESIpos): m/z=483 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.585 (2.22), 1.624 (4.48),1.640 (4.47), 1.683 (7.65), 1.700 (7.81), 2.227 (0.60), 2.319 (10.89),3.478 (16.00), 4.868 (0.43), 4.884 (1.10), 4.899 (1.45), 4.914 (1.05),7.128 (0.49), 7.131 (0.51), 7.149 (1.29), 7.165 (0.97), 7.167 (0.92),7.244 (1.58), 7.251 (1.02), 7.289 (0.56), 7.435 (1.73), 7.449 (1.71),7.884 (1.38), 7.903 (1.20), 8.133 (2.28), 8.162 (2.25), 9.031 (1.27).

Example 745-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 45 and (2R)-2-aminopropan-1-ol.

Example 755-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 45 and (2R)-2-aminobutan-1-ol.

Example 76N-[(2R)-1-amino-1-oxobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 45 and (2R)-2-aminobutanamide.

Example 775-fluoro-N-(heptan-4-yl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 45 and heptan-4-amine.

Example 782-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers Step A2-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzamide,Mixture of Stereoisomers

Synthesized from Intermediate 47 and 2,4-dimethylaniline.

Step B2-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers

2-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzamide(Intermediate from STEP A above, 120 mg, 206 μmol) was dissolved inmethanol (5 mL). 5 drops of hydrochloric acid (0.1N in water) wereadded. The mixture was stirred at room temperature until TLC showedcomplete conversion. Solid sodium carbonate was added and the mixturewas concentrated. The product was purified using column chromatographyto yield the desired product as a mixture of diastereomers.

Example 79N-(2-amino-6-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers Step A tert-butyl{2-[(2-(1-cyclohexylethoxy)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoyl)amino]-3-methylphenyl}carbamate,Mixture of Stereoisomers

Synthesized from Intermediate 47 and tert-butyl(2-amino-3-methylphenyl)carbamate.

Step BN-(2-amino-6-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers

tert-butyl{2-[(2-(1-cyclohexylethoxy)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoyl)amino]-3-methylphenyl}carbamate(160 mg, 234 μmol) was dissolved in DCM (5.0 ml). Hydochloric acid(0.4N, 1 mL) was added and the mixture was stirred vigorously overnight.The mixture was concentrated and purified using preparative TLC to yieldthe desired product as a mixture of stereoisomers.

Example 80N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers Step A tert-butyl{4-[(2-(1-cyclohexylethoxy)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoyl)amino]-3-methylphenyl}carbamate,Mixture of Stereoisomers

Synthesized from Intermediate 47 and tert-butyl(4-amino-3-methylphenyl)carbamate.

Step BN-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 79 from the intermediate above.

Example 812-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers Step A2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzamide,Mixture of Stereoisomers

Synthesized from Intermediate 47 and 2,6-dimethylaniline.

Step B2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 79 from the intermediate above.

¹H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.002 (0.45), 1.063 (0.51), 1.087(0.67), 1.125 (0.81), 1.148 (0.76), 1.179 (0.67), 1.231 (4.24), 1.247(4.06), 1.355 (1.22), 1.455 (4.38), 1.471 (4.40), 1.606 (0.76), 1.628(0.68), 1.695 (1.34), 1.720 (0.91), 1.898 (0.45), 1.928 (0.42), 2.241(16.00), 2.368 (0.40), 3.312 (2.57), 4.354 (0.56), 4.369 (0.85), 4.384(0.54), 4.764 (0.78), 4.780 (1.10), 4.796 (0.74), 5.799 (1.81), 5.814(1.75), 7.120 (7.86), 7.301 (1.33), 7.316 (1.32), 7.558 (1.58), 7.584(1.54), 9.554 (2.02).

Example 825-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers Step A4-{3-[(1S)-1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers

Synthesized from Intermediate 51 and o-toluidine.

Step B5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 78 from the intermediate above.

Example 83N-(2-amino-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pent-4-en-2-yloxy)benzamide,Mixture of Stereoisomers Step A tert-butyl[2-({4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pent-4-en-2-yloxy)benzoyl}amino)-3-methylphenyl]carbamate,Mixture of Stereoisomers

Synthesized from Intermediate 46 and tert-butyl(2-amino-3-methylphenyl)carbamate.

Step BN-(2-amino-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pent-4-en-2-yloxy)benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 78 from the intermediate above.

Example 84N-(2,6-dimethylphenyl)-5-fluoro-4-{3-[(1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2R)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers Step AN-(2,6-dimethylphenyl)-4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-[(2R)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers

Synthesized from Intermediate 51 and 2,6-dimethylaniline.

Step BN-(2,6-dimethylphenyl)-5-fluoro-4-{3-[(1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2R)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 78 from the intermediate above.

Example 85N-(4-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[pent-4-en-2-yloxy]benzamide,Mixture of Stereoisomers Step Atert-butyl[4-({4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[pent-4-en-2-yloxy]benzoyl}amino)-3-methylphenyl]carbamate,Mixture of Stereoisomers

Synthesized from Intermediate 46 and tert-butyl(4-amino-3-methylphenyl)carbamate.

Step BN-(4-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[pent-4-en-2-yloxy]benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 78 from the intermediate above. THFwas used instead of methanol.

Example 865-fluoro-4-{4-methyl-3-[(methylamino)methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamideStep Atert-butyl[(1-{2-fluoro-4-(pentan-3-ylcarbamoyl)-5-[(2S)-pentan-2-yloxy]phenyl}-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]methylcarbamate

Synthesized from Intermediate 49 and pentan-3-amine.

Step B5-fluoro-4-{4-methyl-3-[(methylamino)methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 78 from the intermediate above.

Example 872-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers Step A4-{3-[(benzyloxy)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-(1-cyclohexyl-ethoxy)-N-(2,6-dimethylphenyl)-5-fluorobenzamide,Mixture of Stereoisomers

Synthesized from Intermediate 48 and 2,6-dimethylaniline.

Step B2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide,Mixture of Stereoisomers

4-{3-[(benzyloxy)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-(1-cyclohexyl-ethoxy)-N-(2,6-dimethylphenyl)-5-fluorobenzamide(Intermediate from above, 57.0 mg, 97.2 μmol) was dissolved in methanol(10 mL). The vessel was purged with nitrogen and palladium (10% oncarbon, 20 mg) was added. The vessel was purged with hydrogen and themixture was stirred under an atmosphere of hydrogen overnight. Themixture was filtered through a plug of celite and concentrated. Columnchromatography yielded the desired product (20 mg, 41% yield).

Example 884-[3-(aminomethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methyl-phenyl)-2-[(2S)-pentan-2-yloxy]benzamideStep A4-{3-[(dibenzylamino)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 50 and o-toluidine.

Step B4-[3-(aminomethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methyl-phenyl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 87 from the intermediate above.

Example 89N-[4-amino-2-(trifluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamideStep A4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-nitro-2-(trifluoro-methyl)phenyl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized from Intermediate 44 and 4-nitro-2-(trifluoromethyl)aniline.

LC-MS: m/z=540 [M+H]⁺.

Step BN-[4-amino-2-(trifluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 87 from the intermediate above.

Example 90N-[2-(aminomethyl)-6-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide

N-(2-cyano-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide(Example 25, 50.0 mg, 107 μmol) was dissolved in methanol (10 mL). Thevessel was purged with nitrogen and Raney-Nickel (5 mg) was added. Thevessel was purged with hydrogen and the mixture was stirred under anatmosphere of hydrogen overnight. The mixture was filtered through aplug of celite and concentrated. Preparative TLC yielded the desiredproduct (8 mg, 19% yield).

Example 914-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluorobenzamide,Mixture of Stereoisomers Step A tert-butyl{4-[(2-(1-cyclohexylethoxy)-4-{3-[(1R)-1-(dibenzylamino)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzoyl)amino]-3-methylphenyl}carbamate,Mixture of Stereoisomers

Synthesized from Intermediate 52 and tert-butyl(4-amino-3-methylphenyl)carbamate.

Step BN-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-4-{3-[(1R)-1-(dibenzylamino)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluorobenzamide,Mixture of Stereoisomers

Synthesized analogously to Example 78 (STEP B) from the intermediateabove.

Step C4-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluorobenzamide,Mixture of Stereoisomers

Synthesized analogously to Example 87 (STEP B) from the intermediateabove.

Example 924-(4-cyclopentyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-bromo-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Intermediate 70, 100 mg, 226 μmol),4-cyclopentyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (56.7 mg, 339μmol), tris(dibenzylideneacetone)dipalladium(0) (20.7 mg, 22.6 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39.3 mg, 67.8 μmol),and cesium carbonate (147 mg, 452 μmol) were loaded into a microwavevial. The vial was purged with argon, dioxane (2 mL, degassed) wasadded, and the vial was sealed. The mixture was stirred for 17 h at 110°C. after which LCMS indicated full conversion. The resulting suspensionwas filtered over Celite, washed with ethyl acetate and concentrated.Mass triggered preparative chromatography yielded the desired product(88.0 mg, 66% yield).

LC-MS (Method A): R_(t)=1.35 min, MS (ESIpos): m/z=529 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.426 (4.94), 1.442 (4.94), 1.581(1.48), 1.594 (1.48), 1.610 (1.09), 1.643 (0.59), 1.810 (1.09), 1.822(1.58), 1.828 (1.58), 1.843 (0.99), 1.861 (0.40), 1.919 (0.49), 1.947(1.19), 1.968 (1.28), 2.030 (0.49), 2.048 (1.19), 2.069 (1.28), 2.078(0.99), 2.099 (0.69), 2.171 (1.09), 2.330 (16.00), 2.518 (2.37), 2.522(1.48), 2.668 (0.49), 3.310 (0.59), 3.317 (0.89), 3.321 (1.19), 3.326(0.89), 3.332 (1.58), 3.337 (2.17), 3.344 (3.65), 3.350 (6.22), 3.352(7.01), 3.387 (2.47), 3.391 (1.28), 3.394 (1.09), 3.399 (0.89), 3.404(1.09), 4.346 (0.99), 4.367 (1.58), 4.389 (0.99), 5.304 (0.79), 5.320(0.99), 5.336 (0.79), 7.188 (1.58), 7.208 (3.16), 7.228 (1.98), 7.337(0.49), 7.345 (0.79), 7.369 (0.49), 7.384 (1.38), 7.391 (0.99), 7.406(1.19), 7.422 (0.89), 7.426 (0.79), 7.438 (0.40), 7.459 (0.69), 7.463(0.69), 7.476 (0.49), 7.548 (3.85), 7.564 (2.17), 7.572 (2.27), 9.977(4.15).

Example 93N-(2,6-difluorophenyl)-4-{3-[ethyl(methyl)amino]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-[ethyl(methyl)amino]-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.29 min, MS (ESIpos): m/z=518 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.135 (3.49), 1.153 (7.77), 1.171(3.60), 1.433 (3.84), 1.449 (3.86), 2.085 (16.00), 2.518 (4.47), 2.523(2.85), 2.789 (14.49), 3.138 (1.00), 3.155 (3.02), 3.173 (3.04), 3.191(1.23), 3.204 (13.66), 5.273 (0.63), 5.289 (0.82), 5.305 (0.61), 7.191(1.20), 7.212 (2.46), 7.231 (1.55), 7.387 (0.72), 7.408 (0.88), 7.424(0.49), 7.428 (0.49), 7.532 (1.61), 7.540 (2.09), 7.547 (1.77), 7.566(1.59), 9.932 (3.65).

Example 94N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): Rt=1.20 min; MS (ESIpos): m/z=489 [M+H]⁺.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.358 (3.49), 1.377 (8.19),1.396 (3.72), 1.561 (5.96), 1.645 (3.60), 1.662 (3.62), 2.640 (1.14),2.658 (3.70), 2.677 (3.49), 2.695 (1.02), 3.340 (16.00), 4.906 (0.57),4.922 (0.72), 4.937 (0.55), 6.992 (1.24), 7.006 (0.80), 7.012 (2.38),7.032 (1.69), 7.231 (0.60), 7.237 (0.44), 7.247 (0.40), 7.253 (1.06),7.259 (0.52), 7.454 (1.56), 7.468 (1.52), 8.150 (1.65), 8.178 (1.63),8.977 (1.03).

Example 95N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,Single Stereomer

Synthesized analogously to Example 92 from Intermediate 70 and3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): Rt=1.08 min; MS (ESIpos): m/z=505 [M+H]+.

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.573 (6.88), 1.650 (3.45),1.666 (3.48), 1.689 (6.76), 1.706 (6.92), 2.109 (0.45), 2.125 (0.44),3.487 (16.00), 4.891 (0.75), 4.906 (1.27), 4.922 (1.06), 4.937 (0.58),6.994 (1.25), 7.006 (0.41), 7.015 (2.29), 7.034 (1.63), 7.236 (0.60),7.242 (0.41), 7.257 (0.96), 7.278 (0.57), 7.460 (1.50), 7.474 (1.48),8.150 (1.60), 8.178 (1.58), 8.974 (1.04).

Example 96N-(2,6-difluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 andIntermediate 8.

LC-MS (Method A): R_(t)=1.05 min; MS (ESIpos): m/z=491 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.429 (4.59), 1.444 (4.56), 2.083(7.38), 2.331 (0.53), 2.518 (3.16), 2.522 (2.11), 2.673 (0.53), 3.309(16.00), 4.465 (4.29), 4.480 (4.29), 5.297 (0.75), 5.313 (0.98), 5.329(0.72), 5.741 (1.36), 5.755 (2.97), 5.770 (1.24), 7.191 (1.43), 7.211(2.90), 7.231 (1.81), 7.388 (0.72), 7.408 (0.98), 7.424 (0.56), 7.429(0.56), 7.563 (1.81), 7.578 (3.61), 7.603 (1.92), 10.004 (4.07).

Example 97N-(2,6-difluorophenyl)-4-{3-[(dimethylamino)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 andIntermediate 10.

LC-MS (Method A): R_(t)=0.91 min; MS (ESIneg): m/z=516 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.433 (2.90), 1.448 (2.89), 2.084(0.94), 2.240 (16.00), 2.518 (2.15), 2.523 (1.43), 2.729 (0.95), 2.888(1.16), 3.298 (10.16), 3.446 (4.62), 5.292 (0.46), 5.307 (0.60), 5.323(0.45), 7.192 (0.88), 7.212 (1.85), 7.233 (1.15), 7.388 (0.44), 7.410(0.63), 7.573 (1.70), 7.591 (1.32), 7.596 (1.42), 9.992 (2.69).

Example 98N-(2,6-difluorophenyl)-5-fluoro-4-(4-methyl-5-oxo-3-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-methyl-3-propyl-1H-1,2,4-triazol-5(4H)-one

LC-MS (Method A): R_(t)=1.28 min, MS (ESIpos): m/z=503 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.979 (3.95), 0.997 (9.01), 1.016(4.32), 1.137 (0.83), 1.232 (0.55), 1.429 (3.95), 1.445 (3.95), 1.660(1.29), 1.678 (2.39), 1.696 (2.39), 1.715 (1.29), 2.331 (2.76), 2.337(1.20), 2.518 (16.00), 2.523 (10.85), 2.602 (2.30), 2.621 (3.49), 2.639(2.11), 2.674 (2.85), 2.678 (1.29), 3.233 (14.62), 5.288 (0.64), 5.304(0.83), 5.320 (0.55), 7.190 (1.01), 7.210 (2.02), 7.231 (1.20), 7.407(0.64), 7.541 (1.10), 7.561 (1.93), 7.586 (1.47), 9.977 (2.94).

Example 99N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-methyl-3-methylsulfanyl-1H-1,2,4-triazol-5-one.

LC-MS (Method A): R_(t)=1.26 min; MS (ESIpos): m/z=507 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.435 (3.55), 1.451 (3.52), 2.458(0.77), 2.518 (3.76), 2.523 (2.67), 2.593 (16.00), 2.674 (0.70), 2.888(0.42), 3.207 (12.62), 5.278 (0.56), 5.294 (0.74), 5.310 (0.56), 7.192(1.05), 7.212 (2.15), 7.232 (1.34), 7.387 (0.56), 7.408 (0.70), 7.425(0.46), 7.582 (2.04), 7.601 (1.51), 7.606 (1.72), 9.986 (2.74).

Example 1004-[3-(2-aminoethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and5-(2-aminoethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-onehydrochloride.

LC-MS (Method A): R_(t)=0.90 min; MS (ESIpos): m/z=504 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.021 (0.44), 1.066 (1.47), 1.137(0.59), 1.232 (0.81), 1.435 (10.86), 1.451 (10.57), 1.805 (1.69), 1.900(0.51), 1.921 (1.32), 2.075 (1.10), 2.084 (16.00), 2.096 (0.44), 2.336(1.25), 2.518 (15.49), 2.522 (11.08), 2.539 (1.61), 2.673 (3.16), 2.678(1.54), 2.699 (0.37), 2.729 (0.59), 2.810 (2.79), 2.827 (6.09), 2.845(3.60), 2.888 (0.88), 2.900 (0.59), 2.914 (0.81), 2.930 (0.51), 3.001(3.52), 3.017 (5.58), 3.034 (2.72), 3.080 (1.69), 3.102 (2.64), 3.276(3.74), 3.390 (2.50), 3.808 (0.59), 5.251 (0.73), 5.267 (1.61), 5.283(2.13), 5.299 (1.61), 5.313 (0.73), 5.758 (1.10), 7.193 (3.52), 7.213(7.41), 7.233 (4.70), 7.336 (0.51), 7.346 (0.44), 7.355 (0.81), 7.374(0.95), 7.390 (1.83), 7.411 (2.57), 7.426 (1.83), 7.433 (1.76), 7.442(0.81), 7.447 (0.73), 7.460 (0.44), 7.464 (0.44), 7.554 (3.96), 7.572(6.09), 7.597 (4.40), 8.285 (6.31), 9.986 (1.47).

Example 101N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylamino)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-methyl-3-methylamino-1H-1,2,4-triazol-5-one.

LC-MS (Method A): R_(t)=1.12 min, MS (ESIpos): m/z=490 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.433 (4.32), 1.449 (4.30), 2.085(1.54), 2.518 (2.84), 2.523 (1.99), 2.737 (7.94), 2.749 (7.88), 2.938(0.68), 3.095 (16.00), 5.267 (0.70), 5.282 (0.92), 5.298 (0.68), 5.759(0.95), 6.556 (1.32), 6.568 (1.32), 6.579 (0.45), 7.189 (1.34), 7.210(2.76), 7.231 (1.71), 7.386 (0.69), 7.406 (0.97), 7.427 (0.67), 7.516(2.44), 7.526 (1.78), 7.542 (1.75), 9.894 (4.18).

Example 1024-(3-tert-butyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and5-tert-butyl-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

LC-MS (Method A): R_(t)=1.35 min; MS (ESIpos): m/z=517 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.372 (16.00), 1.432 (1.55), 1.448(1.53), 2.518 (1.06), 2.523 (0.73), 3.415 (5.48), 7.193 (0.47), 7.213(0.97), 7.233 (0.60), 7.566 (1.20), 7.581 (0.62), 7.591 (0.68), 9.975(1.30).

Example 1034-(3-chloro-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-chloro-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.24 min; MS (ESIpos): m/z=495 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.432 (4.98), 1.447 (4.96), 1.646(1.03), 2.084 (1.12), 2.518 (3.17), 2.522 (2.18), 3.262 (0.44), 3.283(16.00), 5.280 (0.79), 5.296 (1.02), 5.312 (0.74), 7.192 (1.69), 7.212(3.24), 7.232 (2.14), 7.367 (1.00), 7.384 (1.51), 7.395 (1.81), 7.410(1.46), 7.431 (0.77), 7.446 (0.41), 7.582 (1.92), 7.597 (2.07), 7.604(2.37), 7.629 (2.10), 10.033 (3.81).

Example 1044-[4-(cyclopropylmethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluoro-phenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-cyclopropylmethyl-3-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIneg): m/z=513 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.362 (0.81), 0.373 (3.14), 0.386(3.31), 0.399 (1.07), 0.500 (1.07), 0.511 (2.62), 0.514 (2.62), 0.520(1.62), 0.530 (2.81), 0.546 (0.76), 1.146 (0.40), 1.158 (0.74), 1.165(0.71), 1.177 (1.02), 1.188 (0.69), 1.196 (0.69), 1.425 (5.50), 1.441(5.43), 2.318 (1.00), 2.323 (1.33), 2.327 (1.19), 2.345 (16.00), 2.518(3.55), 2.535 (0.69), 2.660 (0.79), 2.665 (1.07), 2.669 (0.79), 3.550(4.36), 3.568 (4.21), 5.318 (0.88), 5.335 (1.14), 5.351 (0.83), 7.187(1.71), 7.207 (3.43), 7.228 (2.14), 7.367 (0.52), 7.383 (1.05), 7.404(1.26), 7.420 (0.71), 7.559 (2.48), 7.568 (2.33), 7.583 (4.12), 9.975(4.83).

Example 105N-(2,6-difluorophenyl)-5-fluoro-4-(3-methyl-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-methyl-4-propyl-1H-1,2,4-triazol-5-one.

LC-MS (Method A): R_(t)=1.25 min; MS (ESIpos): m/z=503 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.891 (4.07), 0.909 (8.88), 0.928(4.31), 1.429 (5.60), 1.444 (5.51), 1.629 (1.44), 1.648 (2.78), 1.666(2.52), 1.684 (1.32), 2.313 (16.00), 2.326 (1.53), 2.539 (0.82), 2.669(1.03), 3.603 (2.30), 3.621 (3.59), 3.640 (2.11), 5.295 (0.41), 5.311(0.91), 5.327 (1.17), 5.343 (0.86), 7.191 (1.73), 7.211 (3.45), 7.231(2.11), 7.370 (0.52), 7.387 (1.05), 7.408 (1.25), 7.424 (0.74), 7.560(3.64), 7.577 (2.49), 7.583 (2.52), 9.979 (4.65).

Example 106N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Intermediate 70, 100 mg, 226 μmol),5-(2-hydroxypropan-2-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 7, 53 mg, 339 μmol),tris(dibenzylideneacetone)dipalladium(0) (21 mg, 23 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39 mg, 68 μmol), andcesium carbonate (147 mg, 452 μmol) were loaded into a microwave vial.The vial was purged with argon, dioxane (2 mL, degassed) was added, andthe vial was sealed. The mixture was stirred for 17 h at 110 overnight.The resulting suspension was filtered over Celite, washed with ethylacetate and concentrated. Mass triggered preparative chromatographyyielded the desired product (56 mg, 46% yield).

LC-MS (Method A): R_(t)=1.16 min, MS (ESIpos): m/z=519 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.432 (2.83), 1.447 (2.81), 1.525(16.00), 2.084 (1.68), 2.518 (1.87), 2.522 (1.28), 3.452 (9.33), 5.297(0.45), 5.312 (0.58), 5.328 (0.42), 5.748 (4.50), 5.758 (0.55), 7.193(0.85), 7.214 (1.77), 7.233 (1.12), 7.390 (0.43), 7.410 (0.61), 7.562(1.11), 7.575 (1.96), 7.599 (1.17), 9.982 (2.69).

Example 107N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 andIntermediate 6.

LC-MS (Method A): R_(t)=1.10 min; MS (ESIpos): m/z=505 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.138 (0.94), 1.234 (0.65), 1.263(7.12), 1.281 (16.00), 1.299 (7.00), 1.430 (10.06), 1.446 (10.00), 1.907(0.53), 2.085 (2.12), 2.337 (0.94), 2.518 (10.88), 2.523 (7.71), 2.537(0.47), 2.674 (2.06), 2.679 (0.88), 3.764 (1.88), 3.781 (6.00), 3.800(5.94), 3.817 (1.76), 4.478 (9.24), 4.492 (9.29), 5.301 (0.65), 5.318(1.59), 5.333 (2.06), 5.349 (1.53), 5.365 (0.65), 5.759 (3.12), 5.787(3.12), 5.801 (7.24), 5.816 (2.88), 7.192 (3.12), 7.212 (6.47), 7.233(4.06), 7.373 (0.71), 7.389 (1.59), 7.410 (2.18), 7.426 (1.18), 7.431(1.29), 7.446 (0.53), 7.577 (7.29), 7.594 (4.35), 7.601 (4.65), 10.000(9.41).

Example 108N-(2,6-difluorophenyl)-4-[3-ethyl-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-ethyl-4-(2-hydroxyethyl)-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.13 min; MS (ESIpos): m/z=519 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.104 (0.43), 1.201 (7.34), 1.220(16.00), 1.239 (7.60), 1.433 (8.50), 1.449 (8.45), 2.331 (0.73), 2.518(4.21), 2.522 (2.93), 2.673 (0.83), 2.695 (2.27), 2.713 (6.98), 2.732(6.68), 2.751 (2.06), 3.594 (1.33), 3.607 (4.09), 3.620 (4.85), 3.633(2.13), 3.700 (3.97), 3.713 (5.49), 3.727 (2.27), 5.037 (2.35), 5.050(5.35), 5.063 (2.27), 5.292 (0.57), 5.308 (1.37), 5.324 (1.77), 5.340(1.28), 5.355 (0.50), 7.193 (2.60), 7.214 (5.42), 7.234 (3.39), 7.355(0.50), 7.373 (0.62), 7.389 (1.32), 7.410 (1.85), 7.431 (1.11), 7.447(0.47), 7.562 (4.03), 7.567 (4.69), 7.576 (3.55), 7.592 (3.58), 9.973(8.24).

Example 1094-(3,4-diethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3,4-diethyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.26 min, MS (ESIpos): m/z=503 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.213 (6.77), 1.232 (16.00), 1.251(8.02), 1.432 (4.95), 1.448 (4.93), 2.323 (0.77), 2.327 (1.06), 2.331(0.75), 2.518 (4.18), 2.523 (2.95), 2.665 (0.89), 2.669 (1.33), 2.674(2.10), 2.692 (4.33), 2.711 (4.16), 2.729 (1.25), 3.676 (1.01), 3.694(3.19), 3.712 (3.10), 3.730 (0.94), 5.307 (0.80), 5.323 (1.04), 5.339(0.75), 7.193 (1.54), 7.214 (3.19), 7.234 (2.01), 7.373 (0.46), 7.389(0.92), 7.395 (0.90), 7.410 (1.11), 7.431 (0.60), 7.564 (2.73), 7.583(2.32), 7.588 (2.49), 9.974 (4.64).

Example 1104-(4-cyclopropyl-3-methoxy-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-cyclopropyl-3-methoxy-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIpos): m/z=517 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.927 (8.00), 0.940 (7.45), 1.232(0.82), 1.434 (3.56), 1.450 (3.49), 2.322 (2.94), 2.326 (3.97), 2.331(2.80), 2.336 (1.23), 2.518 (16.00), 2.522 (10.67), 2.664 (3.01), 2.668(4.03), 2.673 (2.87), 2.678 (1.30), 2.801 (1.03), 2.814 (1.37), 2.827(0.96), 3.274 (0.82), 3.932 (1.09), 3.993 (14.70), 5.249 (0.55), 5.266(0.68), 5.281 (0.55), 5.759 (1.78), 7.189 (1.03), 7.210 (2.05), 7.231(1.23), 7.387 (0.48), 7.407 (0.68), 7.530 (1.23), 7.544 (2.53), 7.569(1.44), 9.949 (3.01).

Example 1114-(3-chloro-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-chloro-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.30 min; MS (ESIpos): m/z=509 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.232 (0.55), 1.252 (2.69), 1.270(6.14), 1.288 (2.69), 1.433 (3.38), 1.448 (3.38), 1.647 (0.48), 2.326(4.21), 2.331 (2.97), 2.336 (1.31), 2.518 (16.00), 2.522 (10.76), 2.539(4.90), 2.668 (4.14), 2.673 (2.97), 2.678 (1.31), 3.747 (0.76), 3.765(2.28), 3.783 (2.28), 3.801 (0.69), 5.289 (0.55), 5.305 (0.69), 5.320(0.55), 7.189 (0.83), 7.209 (1.52), 7.230 (0.90), 7.367 (0.48), 7.384(0.83), 7.395 (0.76), 7.600 (1.52), 7.624 (1.72), 10.032 (2.07).

Example 1124-(3-cyclopentyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and3-cyclopentyl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.36 min, MS (ESIneg): m/z=527 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.430 (4.79), 1.446 (4.74), 1.605(0.52), 1.614 (0.84), 1.634 (1.50), 1.643 (1.45), 1.652 (1.64), 1.672(1.22), 1.693 (1.36), 1.698 (1.31), 1.710 (1.41), 1.731 (0.99), 1.768(0.56), 1.786 (0.89), 1.798 (1.03), 1.815 (1.36), 1.833 (0.94), 1.976(0.56), 2.004 (1.41), 2.024 (1.13), 2.035 (0.80), 2.327 (0.75), 2.331(0.56), 2.518 (3.24), 2.523 (2.21), 2.669 (0.75), 2.673 (0.52), 3.103(0.42), 3.166 (1.17), 3.186 (1.64), 3.205 (1.08), 3.225 (0.42), 3.257(16.00), 5.286 (0.75), 5.301 (0.99), 5.317 (0.70), 7.192 (1.50), 7.212(3.05), 7.233 (1.92), 7.346 (0.66), 7.372 (0.52), 7.386 (1.31), 7.394(0.94), 7.409 (1.13), 7.425 (0.66), 7.429 (0.66), 7.460 (0.70), 7.465(0.70), 7.478 (0.47), 7.545 (1.88), 7.559 (3.66), 7.585 (1.92), 7.783(0.42), 9.972 (4.04).

Example 1134-[4-(butan-2-yl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 92 from Intermediate 70 and4-butan-2-yl-3-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.31 min; MS (ESIpos): m/z=517 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.833 (3.02), 0.852 (6.79), 0.870(3.25), 1.233 (0.75), 1.428 (10.34), 1.446 (10.26), 1.714 (0.60), 1.732(0.91), 1.750 (0.68), 1.766 (0.45), 1.959 (0.45), 1.977 (0.53), 2.000(0.53), 2.017 (0.45), 2.312 (13.21), 2.323 (3.09), 2.327 (4.00), 2.332(2.79), 2.336 (1.28), 2.518 (16.00), 2.523 (11.09), 2.539 (2.57), 2.660(1.21), 2.665 (2.72), 2.669 (3.85), 2.673 (2.72), 2.678 (1.21), 3.288(0.45), 3.372 (0.53), 3.962 (0.45), 3.979 (0.68), 4.002 (0.60), 5.331(0.60), 5.346 (0.75), 5.363 (0.60), 7.188 (0.91), 7.208 (1.74), 7.228(1.06), 7.405 (0.60), 7.548 (1.58), 7.572 (2.19), 9.974 (2.04).

Example 1144-[3-(butan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 92 from Intermediate 70 and3-butan-2-yl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.33 min; MS (ESIpos): m/z=517 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.920 (3.85), 0.939 (8.54), 0.957(4.16), 1.228 (8.26), 1.246 (8.38), 1.432 (5.29), 1.448 (5.20), 1.517(0.61), 1.534 (0.98), 1.552 (1.19), 1.569 (1.19), 1.587 (0.73), 1.646(1.74), 1.737 (0.70), 1.753 (1.04), 1.771 (1.16), 1.789 (0.83), 1.806(0.49), 2.323 (0.67), 2.327 (0.89), 2.331 (0.67), 2.665 (0.70), 2.669(0.92), 2.840 (0.83), 2.857 (1.53), 2.874 (1.47), 2.891 (0.73), 3.112(0.58), 3.265 (16.00), 5.290 (0.89), 5.306 (1.13), 5.322 (0.83), 7.193(1.80), 7.214 (3.46), 7.234 (2.11), 7.339 (0.49), 7.350 (0.46), 7.367(1.38), 7.384 (2.20), 7.395 (2.26), 7.410 (1.41), 7.426 (0.86), 7.549(2.17), 7.564 (4.07), 7.588 (2.11), 9.975 (4.19).

Example 115N-(2,6-difluorophenyl)-4-[4-ethyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-ethyl-3-methylsulfanyl-1H-1,2,4-triazol-5-one.

LC-MS (Method A): R_(t)=1.32 min, MS (ESIpos): m/z=521 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.227 (2.93), 1.244 (6.69), 1.263(2.90), 1.437 (3.81), 1.453 (3.78), 2.479 (1.22), 2.518 (2.19), 2.523(1.52), 2.606 (16.00), 3.647 (0.78), 3.665 (2.50), 3.683 (2.45), 3.701(0.74), 5.297 (0.60), 5.313 (0.79), 5.329 (0.59), 7.193 (1.16), 7.214(2.43), 7.234 (1.53), 7.373 (0.47), 7.390 (0.65), 7.395 (0.63), 7.411(0.86), 7.431 (0.52), 7.582 (1.62), 7.607 (1.95), 7.611 (1.74), 7.627(1.43), 9.980 (3.30).

Example 116N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-methoxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 92 from Intermediate 70 andIntermediate 11.

LC-MS (Method A): R_(t)=1.23 min; MS (ESIpos): m/z=519 [M+H]⁺.

Example 117N-(2,6-difluorophenyl)-4-[4-ethyl-5-oxo-3-(propan-2-yloxy)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-ethyl-3-isopropoxy-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.40 min; MS (ESIpos): m/z=533 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.193 (2.96), 1.211 (6.72), 1.229(3.18), 1.396 (15.67), 1.411 (16.00), 1.437 (3.84), 1.453 (3.75), 2.518(3.86), 2.523 (2.64), 3.558 (0.81), 3.575 (2.54), 3.594 (2.48), 3.611(0.75), 4.976 (0.42), 4.991 (1.04), 5.007 (1.43), 5.022 (1.05), 5.283(0.62), 5.299 (0.78), 5.315 (0.59), 7.191 (1.16), 7.211 (2.34), 7.231(1.46), 7.386 (0.72), 7.407 (0.80), 7.428 (0.51), 7.549 (1.79), 7.556(1.58), 7.573 (2.36), 9.939 (3.20).

Example 118

4-(4-benzyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 70 and4-benzyl-3-methyl-1H-1,2,4-triazol-5-one.

LC-MS (Method A): R_(t)=1.36 min; MS (ESIpos): m/z=551 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.433 (5.20), 1.449 (5.14), 2.229(16.00), 2.327 (1.01), 2.331 (0.73), 2.518 (4.26), 2.523 (2.99), 2.669(1.05), 2.673 (0.73), 4.933 (6.79), 5.324 (0.81), 5.340 (1.05), 5.356(0.78), 7.195 (1.62), 7.215 (3.41), 7.235 (2.18), 7.324 (3.48), 7.344(5.91), 7.358 (1.93), 7.360 (1.76), 7.374 (0.63), 7.396 (4.43), 7.402(1.66), 7.414 (4.14), 7.417 (2.84), 7.433 (1.88), 7.581 (2.31), 7.606(2.55), 7.613 (2.26), 7.628 (2.03), 10.001 (4.88).

Example 119N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 andIntermediate 8.

LC-MS (Method A): R_(t)=1.11 min; MS (ESIpos): m/z=507 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.435 (4.35), 1.451 (4.32), 2.084(2.30), 2.332 (0.82), 2.518 (4.49), 2.522 (3.03), 2.539 (0.42), 2.673(0.81), 3.311 (16.00), 4.467 (4.30), 4.482 (4.39), 5.328 (0.67), 5.344(0.84), 5.360 (0.61), 5.739 (1.40), 5.753 (3.18), 5.758 (0.71), 5.768(1.32), 7.332 (0.40), 7.336 (0.44), 7.355 (1.02), 7.372 (0.63), 7.380(0.77), 7.388 (0.54), 7.402 (0.44), 7.409 (1.00), 7.422 (1.15), 7.433(2.15), 7.439 (2.69), 7.453 (0.52), 7.553 (1.69), 7.577 (2.42), 7.588(1.55), 10.065 (3.45).

Example 120N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 andIntermediate 7.

LC-MS (Method A): R_(t)=1.22 min, MS (ESIpos): m/z=535 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.437 (2.92), 1.453 (2.88), 1.526(16.00), 2.084 (5.04), 2.322 (0.47), 2.326 (0.63), 2.331 (0.44), 2.518(3.19), 2.522 (2.07), 2.664 (0.48), 2.668 (0.63), 2.673 (0.44), 3.299(0.48), 3.453 (9.26), 5.326 (0.44), 5.342 (0.57), 5.358 (0.42), 5.750(4.37), 7.355 (0.79), 7.374 (0.44), 7.382 (0.52), 7.410 (0.67), 7.424(0.84), 7.435 (1.49), 7.441 (1.76), 7.549 (1.11), 7.573 (1.77), 7.586(1.01), 10.046 (2.47).

Example 121N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-N-(2-chloro-6-fluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Intermediate 71, 100 mg, 218 μmol),4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 6, 46.8 mg, 327 μmol),tris(dibenzylideneacetone)dipalladium(0) (20 mg, 22 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38 mg, 65 μmol), andcesium carbonate (142 mg, 436 μmol) were loaded into a microwave vial.The vial was purged with argon, dioxane (2 mL, degassed) was added, andthe vial was sealed. The mixture was stirred for 17 h at 110° C. Theresulting suspension was filtered over Celite, washed with ethyl acetateand concentrated. Mass triggered preparative chromatography yielded thedesired product (47.0 mg, 40% yield).

LC-MS (Method A): R_(t)=1.16 min; MS (ESIpos): m/z=521 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.137 (0.43), 1.233 (0.49), 1.264(6.16), 1.282 (13.73), 1.300 (6.05), 1.436 (9.08), 1.451 (8.92), 2.084(8.00), 2.322 (2.38), 2.326 (3.08), 2.331 (2.22), 2.518 (16.00), 2.522(10.27), 2.664 (2.43), 2.669 (3.14), 2.673 (2.27), 3.764 (1.73), 3.782(5.24), 3.800 (5.08), 3.818 (1.51), 4.479 (8.00), 4.493 (8.00), 5.331(0.59), 5.347 (1.41), 5.363 (1.78), 5.380 (1.24), 5.396 (0.49), 5.759(1.24), 5.789 (2.65), 5.803 (5.89), 5.817 (2.38), 7.337 (0.97), 7.356(2.16), 7.372 (1.35), 7.380 (1.62), 7.388 (1.14), 7.408 (2.00), 7.422(2.43), 7.433 (4.54), 7.439 (5.08), 7.453 (1.14), 7.550 (3.41), 7.575(3.57), 7.588 (3.19), 7.602 (2.92), 10.065 (7.03).

Example 122N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 andIntermediate 9.

LC-MS (Method A): R_(t)=1.16 min; MS (ESIpos): m/z=521 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.437 (0.84), 1.457 (1.55), 1.474(1.20), 2.084 (0.41), 2.522 (0.55), 3.331 (16.00), 3.341 (2.70), 5.821(0.52), 5.836 (0.51), 7.440 (0.44), 7.575 (0.40), 10.056 (0.62).

Example 1235-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 72 andIntermediate 8.

LC-MS (Method A): R_(t)=1.01 min; MS (ESIpos): m/z=500 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.444 (4.25), 1.460 (4.23), 2.084(2.42), 2.220 (10.56), 2.331 (0.41), 2.518 (2.63), 2.522 (1.71), 2.539(0.80), 2.669 (0.58), 2.673 (0.41), 3.312 (14.96), 3.321 (2.01), 3.860(16.00), 4.468 (2.85), 4.482 (2.83), 5.363 (0.67), 5.378 (0.86), 5.395(0.63), 5.742 (0.76), 5.756 (1.84), 5.770 (0.69), 6.932 (1.90), 6.946(1.94), 7.552 (1.84), 7.569 (3.24), 7.594 (2.25), 7.968 (2.48), 7.981(2.33), 9.663 (2.57).

Example 1244-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 72 andIntermediate 6.

LC-MS (Method A): R_(t)=1.04 min; MS (ESIneg): m/z=512 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.265 (2.79), 1.283 (6.36), 1.301(2.76), 1.445 (4.67), 1.461 (4.64), 2.084 (1.75), 2.220 (11.39), 2.322(0.54), 2.326 (0.72), 2.331 (0.50), 2.518 (3.15), 2.522 (2.07), 2.664(0.55), 2.668 (0.73), 2.673 (0.53), 3.765 (0.77), 3.783 (2.39), 3.801(2.36), 3.820 (0.83), 3.860 (16.00), 4.479 (3.13), 4.494 (3.09), 5.382(0.72), 5.398 (0.94), 5.414 (0.68), 5.790 (0.86), 5.804 (2.02), 5.818(0.80), 6.933 (2.05), 6.946 (2.10), 7.568 (4.64), 7.583 (2.02), 7.592(2.39), 7.969 (2.59), 7.981 (2.48), 9.661 (2.82).

Example 1255-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 72 andIntermediate 7.

LC-MS (Method A): R_(t)=1.11 min, MS (ESIpos): m/z=528 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.447 (3.41), 1.463 (3.40), 1.526(16.00), 2.084 (2.52), 2.221 (8.01), 2.322 (0.45), 2.326 (0.59), 2.331(0.42), 2.518 (2.97), 2.522 (1.92), 2.539 (1.85), 2.664 (0.45), 2.668(0.60), 2.673 (0.43), 3.454 (9.56), 3.861 (10.42), 5.363 (0.52), 5.378(0.68), 5.394 (0.49), 5.750 (3.64), 5.759 (0.75), 6.934 (1.46), 6.947(1.49), 7.550 (1.40), 7.566 (2.80), 7.591 (1.59), 7.969 (1.78), 7.983(1.66), 9.645 (2.04).

Example 1265-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 72 andIntermediate 9.

LC-MS (Method A): R_(t)=1.07 min; MS (ESIpos): m/z=514 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.447 (1.23), 1.458 (2.02), 1.462(1.44), 1.475 (1.63), 2.084 (0.59), 2.221 (2.83), 2.518 (0.60), 3.331(16.00), 3.342 (3.71), 5.822 (0.74), 5.836 (0.72), 6.934 (0.51), 6.947(0.52), 7.547 (0.48), 7.562 (0.52), 7.568 (0.67), 7.593 (0.60), 7.969(0.65), 7.982 (0.62), 9.653 (0.69).

Example 1275-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Intermediate 73, 100 mg, 228 μmol),5-(hydroxymethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 8, 44 mg, 342 μmol),tris(dibenzylideneacetone)dipalladium(0) (21 mg, 23 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg, 68 μmol), andcesium carbonate (149 mg, 456 μmol) were loaded into a microwave vial.The vial was purged with argon, dioxane (2 mL, degassed) was added, andthe vial was sealed. The mixture was stirred for 17 h at 110 overnight.The resulting suspension was filtered over Celite, washed with ethylacetate and concentrated. Mass triggered preparative chromatographyyielded the desired product (75 mg, 67% yield).

LC-MS (Method A): R_(t)=1.10 min; MS (ESIpos): m/z=487 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.429 (1.77), 1.444 (1.76), 2.084(0.46), 2.272 (4.04), 2.518 (0.63), 2.522 (0.42), 3.312 (5.92), 3.331(16.00), 4.467 (1.28), 4.482 (1.28), 5.755 (0.87), 7.117 (0.60), 7.121(0.58), 7.134 (0.64), 7.247 (0.40), 7.557 (0.88), 7.561 (1.14), 7.572(0.77), 7.586 (0.93), 9.825 (1.07).

Example 1284-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 73 andIntermediate 6.

LC-MS (Method A): R_(t)=1.15 min; MS (ESIpos): m/z=501 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.265 (4.21), 1.283 (9.63), 1.301(4.15), 1.429 (7.02), 1.445 (6.97), 2.084 (3.62), 2.272 (16.00), 2.322(0.49), 2.326 (0.63), 2.331 (0.45), 2.518 (2.93), 2.522 (1.84), 2.539(0.57), 2.664 (0.49), 2.668 (0.64), 2.673 (0.45), 3.765 (1.15), 3.783(3.62), 3.801 (3.50), 3.818 (1.04), 4.479 (4.44), 4.493 (4.41), 5.345(0.45), 5.361 (1.10), 5.377 (1.41), 5.393 (1.03), 5.789 (1.19), 5.803(2.91), 5.817 (1.10), 7.101 (0.95), 7.117 (2.38), 7.122 (2.32), 7.134(2.57), 7.144 (1.44), 7.228 (1.11), 7.241 (1.24), 7.247 (1.61), 7.261(1.24), 7.267 (0.79), 7.280 (0.67), 7.559 (3.84), 7.571 (3.09), 7.584(5.27), 9.824 (4.24).

Example 1295-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 73 andIntermediate 7.

LC-MS (Method A): R_(t)=1.22 min; MS (ESIpos): m/z=515 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.431 (3.30), 1.447 (3.27), 1.526(16.00), 2.084 (1.07), 2.272 (7.50), 2.518 (1.61), 2.522 (1.04), 3.454(10.04), 3.566 (0.51), 5.341 (0.51), 5.357 (0.66), 5.373 (0.48), 5.750(3.35), 7.103 (0.45), 7.119 (1.12), 7.123 (1.08), 7.136 (1.20), 7.145(0.67), 7.228 (0.52), 7.242 (0.59), 7.248 (0.75), 7.262 (0.58), 7.555(2.56), 7.568 (1.40), 7.580 (1.72), 9.805 (1.93).

Example 1305-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 73 andIntermediate 9.

LC-MS (Method A): R_(t)=1.15 min; MS (ESIpos): m/z=501 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.431 (1.09), 1.447 (1.14), 1.458(1.53), 1.474 (1.49), 2.084 (0.64), 2.272 (2.44), 2.518 (0.53), 3.332(16.00), 3.342 (3.43), 5.821 (0.66), 5.836 (0.63), 7.551 (0.49), 7.558(0.64), 7.566 (0.47), 7.583 (0.56), 9.813 (0.65).

Example 131N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 74 andIntermediate 8.

LC-MS (Method A): R_(t)=1.14 min; MS (ESIpos): m/z=523 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.137 (0.85), 1.433 (3.02), 1.449(2.96), 1.526 (1.59), 2.272 (0.80), 2.322 (2.56), 2.326 (3.42), 2.331(2.39), 2.518 (16.00), 2.522 (10.19), 2.664 (2.56), 2.668 (3.42), 2.673(2.45), 3.311 (11.79), 3.453 (1.02), 4.468 (1.99), 4.482 (2.05), 5.354(0.40), 5.369 (0.51), 5.756 (0.97), 5.770 (0.46), 7.405 (0.57), 7.426(0.46), 7.528 (1.48), 7.552 (1.71), 7.581 (1.99), 7.601 (1.25), 10.227(1.31).

Example 132N-(2,6-dichlorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 74 andIntermediate 6.

LC-MS (Method A): R_(t)=1.18 min, MS (ESIpos): m/z=537 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.137 (0.53), 1.265 (7.31), 1.283(16.00), 1.301 (7.10), 1.357 (0.46), 1.374 (0.40), 1.436 (12.55), 1.451(12.45), 1.526 (0.53), 1.987 (0.51), 2.084 (9.22), 2.518 (6.57), 2.522(4.25), 2.539 (0.68), 3.566 (2.01), 3.766 (2.03), 3.784 (6.24), 3.802(6.13), 3.820 (1.88), 4.481 (8.03), 4.495 (7.97), 5.353 (0.82), 5.370(1.92), 5.385 (2.49), 5.401 (1.80), 5.416 (0.72), 5.758 (2.13), 5.791(2.03), 5.806 (4.14), 5.820 (1.90), 7.386 (3.02), 7.406 (4.92), 7.426(4.21), 7.526 (5.85), 7.551 (5.81), 7.583 (15.94), 7.589 (5.81), 7.603(15.87), 10.226 (7.55).

Example 133N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

4-Bromo-N-(2,6-dichlorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Intermediate 74, 200 mg, 421 μmol),5-(2-hydroxypropan-2-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 7, 99 mg, 631 μmol),tris(dibenzylideneacetone)dipalladium(0) (42 mg, 42 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg, 126 μmol), andcesium carbonate (274 mg, 842 μmol) were loaded into a microwave vial.The vial was purged with argon, dioxane (4 mL, degassed) was added, andthe vial was sealed. The mixture was stirred for 17 h at 110° C.overnight. The resulting suspension was filtered over Celite, washedwith ethyl acetate and concentrated. Preparative chromatography(water+0.5% formic acid/acetonitrile gradient) yielded the desiredproduct (81 mg, 31% yield).

LC-MS (Method A): R_(t)=1.25 min; MS (ESIpos): m/z=551 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.390 (0.51), 1.405 (0.54), 1.439(3.53), 1.455 (3.51), 1.527 (16.00), 2.084 (0.57), 3.455 (9.05), 5.350(0.55), 5.366 (0.71), 5.382 (0.51), 5.751 (2.97), 7.388 (0.80), 7.408(1.36), 7.428 (1.11), 7.526 (1.56), 7.550 (1.59), 7.572 (1.54), 7.585(5.04), 7.605 (3.12), 10.207 (2.30).

Example 134N-(2,6-dichlorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 74 andIntermediate 9.

LC-MS (Method A): R_(t)=1.18 min; MS (ESIpos): m/z=537 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.437 (1.52), 1.455 (1.87), 1.458(2.15), 1.475 (1.80), 2.522 (0.41), 3.331 (16.00), 3.343 (3.88), 4.792(0.45), 5.822 (0.81), 5.837 (0.76), 7.407 (0.55), 7.427 (0.44), 7.527(0.64), 7.552 (0.66), 7.569 (0.61), 7.584 (2.15), 7.604 (1.24), 10.216(0.92).

Example 135N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 76 andIntermediate 8.

LC-MS (Method A): R_(t)=1.22 min; MS (ESIneg): m/z=479 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.860 (3.52), 0.879 (8.40), 0.897(3.94), 1.310 (4.20), 1.324 (4.23), 1.351 (0.50), 1.366 (0.45), 1.376(0.53), 1.394 (0.47), 1.409 (0.49), 1.427 (0.42), 1.440 (0.44), 1.446(0.46), 1.465 (0.46), 1.594 (0.44), 1.606 (0.56), 1.618 (0.44), 1.755(0.40), 1.769 (0.43), 1.780 (0.43), 2.518 (1.71), 2.522 (1.17), 3.305(16.00), 4.460 (4.12), 4.474 (4.10), 4.624 (0.72), 4.638 (0.73), 5.728(1.22), 5.742 (2.79), 5.757 (1.12), 7.336 (0.45), 7.356 (1.12), 7.375(0.75), 7.380 (0.89), 7.409 (1.65), 7.419 (1.61), 7.425 (1.94), 7.440(2.05), 7.445 (1.93), 7.462 (0.68), 7.661 (1.39), 7.687 (1.37), 9.838(3.19).

Example 136N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 76 andIntermediate 9.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIpos): m/z=495 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.864 (1.26), 0.882 (3.04), 0.901(1.43), 1.315 (1.50), 1.330 (1.53), 1.453 (2.64), 1.470 (2.62), 2.518(0.45), 3.333 (16.00), 3.337 (7.21), 4.765 (0.42), 4.781 (0.60), 4.797(0.42), 5.806 (1.01), 5.820 (1.00), 7.358 (0.44), 7.382 (0.55), 7.407(0.75), 7.421 (0.68), 7.442 (0.70), 7.447 (0.68), 7.665 (0.50), 7.691(0.48), 9.831 (1.25).

Example 137N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 76 andIntermediate 7.

LC-MS (Method A): R_(t)=1.35 min; MS (ESIpos): m/z=509 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.867 (2.19), 0.885 (5.11), 0.903(2.45), 1.318 (2.72), 1.333 (2.73), 1.521 (16.00), 2.522 (0.76), 3.448(9.18), 4.627 (0.49), 4.642 (0.47), 5.734 (3.86), 7.357 (0.74), 7.377(0.53), 7.382 (0.63), 7.406 (0.81), 7.419 (1.17), 7.430 (1.03), 7.442(1.31), 7.447 (1.22), 7.463 (0.44), 7.665 (0.89), 7.691 (0.87), 9.824(2.15).

Example 1385-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 77 andIntermediate 8.

LC-MS (Method A): R_(t)=1.13 min; MS (ESIpos): m/z=474 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.871 (3.46), 0.889 (7.84), 0.908(3.93), 1.316 (6.96), 1.331 (7.02), 1.350 (0.46), 1.369 (0.56), 1.394(0.72), 1.411 (0.79), 1.428 (0.79), 1.447 (0.67), 1.453 (0.64), 1.472(0.63), 1.595 (0.50), 1.615 (0.58), 1.629 (0.78), 1.639 (0.56), 1.653(0.61), 1.741 (0.58), 1.756 (0.59), 1.767 (0.62), 1.775 (0.53), 2.208(13.26), 2.327 (0.51), 2.668 (0.50), 3.306 (15.25), 3.876 (16.00), 4.461(4.18), 4.475 (4.27), 4.641 (0.59), 4.657 (1.16), 4.672 (1.14), 4.688(0.58), 5.728 (1.18), 5.742 (2.53), 5.757 (1.14), 6.942 (2.40), 6.955(2.46), 7.408 (2.20), 7.423 (2.20), 7.691 (2.61), 7.718 (2.55), 7.965(2.82), 7.979 (2.68), 9.634 (3.42).

Example 1395-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 77 andIntermediate 9.

LC-MS (Method A): R_(t)=1.18 min, MS (ESIpos): m/z=488 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.875 (3.28), 0.893 (7.60), 0.912(3.66), 1.321 (6.50), 1.336 (6.60), 1.372 (0.50), 1.397 (0.68), 1.415(0.79), 1.430 (0.84), 1.453 (7.23), 1.470 (7.04), 1.596 (0.46), 1.616(0.51), 1.630 (0.72), 1.640 (0.48), 1.655 (0.54), 1.744 (0.54), 1.758(0.50), 1.770 (0.53), 1.777 (0.45), 2.207 (12.32), 2.326 (0.55), 2.522(1.74), 2.668 (0.57), 3.877 (16.00), 4.641 (0.54), 4.657 (1.03), 4.672(1.02), 4.687 (0.51), 4.765 (1.07), 4.780 (1.55), 4.796 (1.05), 5.806(2.38), 5.820 (2.32), 6.943 (2.22), 6.956 (2.29), 7.405 (2.00), 7.421(1.98), 7.693 (2.49), 7.720 (2.41), 7.966 (2.72), 7.979 (2.61), 9.632(3.13).

Example 1405-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

4-Bromo-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide(Intermediate 77, 200 mg, 470 μmol),5-(2-hydroxypropan-2-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate 7, 67 mg, 427 μmol),tris(dibenzylideneacetone)dipalladium(0) (39 mg, 43 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74 mg, 128 μmol), andcesium carbonate (278 mg, 855 μmol) were loaded into a microwave vial.The vial was purged with argon, dioxane (2 mL, degassed) was added, andthe vial was sealed. The mixture was stirred for 17 h at 110° C.overnight. The resulting suspension was filtered over Celite, washedwith ethyl acetate and concentrated. Preparative chromatography(water+0.1% formic acid/acetonitrile gradient) yielded the desiredproduct (35.0 mg, 15% yield).

LC-MS (Method A): R_(t)=1.24 min, MS (ESIpos): m/z=502 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.878 (2.20), 0.896 (4.86), 0.915(2.44), 1.324 (4.31), 1.339 (4.36), 1.401 (0.51), 1.416 (0.62), 1.433(0.61), 1.454 (0.54), 1.473 (0.49), 1.522 (16.00), 1.618 (0.42), 1.632(0.54), 1.645 (0.42), 1.747 (0.43), 1.772 (0.44), 2.207 (8.28), 3.449(8.87), 3.878 (9.62), 4.660 (0.77), 4.675 (0.75), 5.734 (3.35), 6.944(1.52), 6.956 (1.55), 7.414 (1.37), 7.429 (1.37), 7.694 (1.55), 7.721(1.52), 7.967 (1.70), 7.979 (1.65), 9.630 (2.22).

Example 1415-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 78 andIntermediate 8.

LC-MS (Method A): R_(t)=1.21 min; MS (ESIpos): m/z=461 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.860 (3.66), 0.878 (8.27), 0.896(4.12), 1.293 (7.16), 1.308 (7.30), 1.329 (0.45), 1.346 (0.60), 1.354(0.53), 1.363 (0.62), 1.372 (0.71), 1.379 (0.59), 1.389 (0.69), 1.398(0.55), 1.405 (0.62), 1.411 (0.61), 1.422 (0.63), 1.436 (0.66), 1.455(0.64), 1.557 (0.56), 1.577 (0.62), 1.591 (0.82), 1.602 (0.60), 1.615(0.59), 1.715 (0.59), 1.730 (0.63), 1.740 (0.62), 2.084 (1.38), 2.276(13.44), 2.327 (0.41), 3.305 (16.00), 4.459 (4.21), 4.473 (4.23), 4.575(0.62), 4.590 (1.18), 4.605 (1.16), 4.621 (0.59), 5.725 (1.16), 5.739(2.58), 5.754 (1.09), 7.106 (0.86), 7.127 (3.02), 7.144 (2.49), 7.229(0.90), 7.244 (1.07), 7.249 (1.34), 7.264 (1.06), 7.282 (0.50), 7.363(2.31), 7.378 (2.28), 7.607 (2.66), 7.633 (2.62), 9.656 (3.60).

Example 1425-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 78 andIntermediate 9.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIpos): m/z=475 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.863 (4.32), 0.881 (9.61), 0.899(4.83), 1.297 (8.50), 1.312 (8.60), 1.332 (0.58), 1.350 (0.75), 1.375(0.91), 1.392 (1.00), 1.411 (0.98), 1.453 (9.31), 1.469 (9.07), 1.544(0.40), 1.558 (0.68), 1.578 (0.79), 1.591 (1.01), 1.602 (0.76), 1.616(0.74), 1.647 (0.67), 1.703 (0.49), 1.717 (0.75), 1.733 (0.79), 1.744(0.78), 1.777 (0.44), 2.084 (0.91), 2.276 (16.00), 2.327 (0.48), 2.670(0.43), 4.575 (0.76), 4.590 (1.44), 4.605 (1.44), 4.620 (0.75), 4.764(1.45), 4.779 (2.12), 4.795 (1.42), 5.803 (3.14), 5.818 (3.06), 7.108(1.00), 7.127 (3.69), 7.145 (3.08), 7.230 (1.07), 7.245 (1.30), 7.250(1.63), 7.264 (1.32), 7.284 (0.62), 7.360 (2.96), 7.375 (2.92), 7.393(0.65), 7.608 (3.10), 7.634 (3.03), 9.647 (4.40).

Example 1435-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 78 andIntermediate 7.

LC-MS (Method A): R_(t)=1.34 min, MS (ESIneg): m/z=487 [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.866 (2.19), 0.884 (4.82), 0.903(2.44), 1.300 (4.32), 1.315 (4.34), 1.353 (0.43), 1.360 (0.42), 1.378(0.51), 1.395 (0.56), 1.411 (0.57), 1.436 (0.48), 1.455 (0.48), 1.520(16.00), 1.559 (0.43), 1.579 (0.45), 1.593 (0.57), 1.603 (0.42), 1.647(0.42), 1.720 (0.42), 1.736 (0.43), 1.745 (0.43), 2.275 (8.06), 3.447(8.88), 4.593 (0.76), 4.608 (0.75), 5.730 (3.40), 7.108 (0.55), 7.128(1.93), 7.146 (1.62), 7.231 (0.57), 7.250 (0.85), 7.264 (0.71), 7.367(1.65), 7.383 (1.80), 7.608 (1.55), 7.634 (1.51), 9.640 (2.25).

Example 1445-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 79 andIntermediate 8.

LC-MS (Method A): R_(t)=1.22 min; MS (ESIpos): m/z=423 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.867 (7.77), 0.885 (16.00), 0.903(8.54), 1.254 (6.10), 1.269 (6.10), 1.391 (1.79), 1.405 (2.17), 1.422(2.18), 1.439 (1.52), 1.524 (1.20), 1.540 (1.79), 1.557 (2.08), 1.574(1.86), 1.590 (1.60), 1.612 (1.00), 1.633 (0.89), 1.648 (0.79), 1.658(0.77), 2.084 (0.91), 2.328 (0.59), 2.669 (0.58), 3.291 (12.37), 3.779(0.87), 3.799 (0.87), 4.445 (3.36), 4.457 (3.37), 4.569 (0.62), 4.583(1.13), 4.597 (1.12), 4.612 (0.61), 5.731 (1.69), 7.303 (2.01), 7.318(1.97), 7.584 (2.05), 7.611 (2.04), 7.901 (1.46), 7.923 (1.42).

Example 1455-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide

Synthesized analogously to Example 92 from Intermediate 79 andIntermediate 7.

LC-MS (Method A): R_(t)=1.35 min; MS (ESIpos): m/z=451 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.866 (3.28), 0.875 (3.04), 0.885(7.22), 0.893 (5.83), 0.903 (3.83), 0.911 (2.71), 1.261 (4.33), 1.276(4.33), 1.358 (0.43), 1.368 (0.70), 1.375 (0.63), 1.386 (0.93), 1.394(0.77), 1.403 (1.03), 1.409 (1.03), 1.423 (1.07), 1.428 (1.04), 1.442(0.79), 1.507 (16.00), 1.527 (0.83), 1.541 (0.97), 1.546 (0.89), 1.559(1.07), 1.576 (0.93), 1.593 (0.80), 1.600 (0.54), 1.614 (0.50), 1.640(0.47), 1.649 (0.41), 1.655 (0.40), 1.665 (0.45), 2.084 (2.21), 3.434(9.28), 3.783 (0.46), 3.804 (0.46), 4.588 (0.65), 4.603 (0.65), 5.718(3.35), 7.310 (1.36), 7.325 (1.34), 7.592 (1.62), 7.619 (1.58), 7.896(0.88), 7.918 (0.86).

Example 146N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 75 and3-ethyl-4-methyl-1H-1,2,4-triazol-5(4H)-one.

LC-MS (Method A): R_(t)=1.27 min, MS (ESIpos): m/z=471 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.237 (4.30), 1.256 (9.64), 1.275(4.45), 1.496 (3.45), 1.512 (3.43), 2.085 (1.81), 2.518 (1.43), 2.523(0.98), 2.652 (1.28), 2.671 (4.17), 2.689 (3.89), 2.708 (1.12), 3.231(16.00), 5.260 (0.57), 5.276 (0.74), 5.292 (0.55), 7.183 (1.03), 7.203(2.12), 7.223 (1.29), 7.375 (0.58), 7.395 (0.90), 7.412 (0.44), 7.733(4.45), 7.893 (1.89), 9.684 (3.29).

Example 1475-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(tetrahydrofuran-3-yl)benzamide,Mixture of Stereoisomers

5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzoicacid (Intermediate 82, 150 mg, 395 μmol) and tetrahydrofuran-3-amine(44.0 mg, 505 μmol) were dissolved in dichloromethane (20 mL).Triethylamine (167 μL, 1.2 mmol) was added, followed by HATU (190 mg,499 μmol). The mixture was stirred at room temperature overnight. Thesolvent was removed and the mixture was purified using preparative TLCto yield 66 mg of desired product (37% yield).

Example 1485-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

Synthesized analogously to Example 147 from Intermediate 82 and(2R)-2-aminopropan-1-ol.

Example 1495-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-(1H-pyrazol-3-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 and1H-pyrazol-3-amine.

Example 1505-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-2-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 andpyridin-2-amine.

Example 1515-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-4-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 andpyridin-4-amine.

Example 1525-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-(1-methylpiperidin-4-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 and1-methylpiperidin-4-amine.

Example 1535-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-(tetrahydro-2H-pyran-4-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 andtetrahydro-2H-pyran-4-amine.

Example 1545-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-(pyrimidin-4-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 andpyrimidin-4-amine.

Example 1555-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1,3-oxazol-2-yl)benzamide

Synthesized analogously to Example 147 from Intermediate 82 and1,3-oxazol-2-amine.

Example 1565-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

Synthesized analogously to Example 147 from Intermediate 82 and(2R)-2-aminobutan-1-ol.

Example 157N-cyclopentyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

Synthesized analogously to Example 147 from Intermediate 82 andcyclopentanamine.

MS (ESIpos): m/z=446 [M+H]⁺.

Example 158N-cyclohexyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

Synthesized analogously to Example 147 from Intermediate 82 andcyclohexanamine.

MS (ESIpos): m/z=460 [M+H]⁺.

Example 1595-fluoro-N-(2-hydroxypropyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 147 from Intermediate 82 and1-aminopropan-2-ol

Example 1605-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-phenylbenzamide

Synthesized analogously to Example 147 from Intermediate 82 and aniline.

MS (ESIneg): m/z=453 [M−H]⁻.

Example 1615-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-(pyrimidin-2-yl)benzamide

5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}benzoicacid (Intermediate 82, 150 mg, 395 μmol) was dissolved indichloromethane (5 mL). Oxalyl chloride (140 μl, 1.6 mmol) was added,followed by DMF (30 μl, 390 μmol). The mixture was stirred at roomtemperature for 3 h. The mixture was concentrated. The resulting residuewas suspended in dichloromethane (5 mL), pyrimidin-2-amine (60.0 mg, 631μmol) was added and the mixture was stirred overnight. The solvent wasremoved and the mixture was purified by column chromatography to yieldthe desired product (15 mg, 8% yield).

Example 162N-[(2R)-1-aminopropan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamideStep A5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-[(2R)-1-oxopropan-2-yl]benzamide

5-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide(Example 148, 120 mg, 275 μmol) was dissolved in DCM. Dess-Martinperiodinane (1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 233mg, 550 μmol) was added and the mixture was stirred at room temperaturefor 4 h. The mixture was filtered and the solution was concentrated toyield the desired intermediate which was directly used in the next step.

Step BN-[(2R)-1-aminopropan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methyl-pentan-2-yl]oxy}-N-[(2R)-1-oxopropan-2-yl]benzamide(Intermediate from above, 75.0 mg, 173 μmol) was dissolved in drymethanol (10 mL). Zinc chloride was added (1M solution in ether, 0.32mL, 0.32 mmol) followed by ammonium formate (110 mg, 1.6 mmol). Themixture was stirred at room temperature for 1 h. Sodium cyanoborohydride(20 mg, 0.32 mmol) was added and the mixture was stirred at roomtemperature for 2 h. The mixture was concentrated and purified byprepHPLC to yield the desired product (10 mg, 14% yield).

MS (ESIpos): m/z=436 [M+H]⁺.

Example 163N-[(2R)-1-aminobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide

Synthesized analogously to Example 162 from Example 156 in two steps.

Example 1645-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(piperidin-4-yl)benzamide,Salt with Hydrochloric Acid Step A tert-butyl4-[(5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzoyl)amino]piperidine-1-carboxylate

Synthesized analogously to Example 147 from Intermediate 82 andtert-butyl 4-aminopiperidine-1-carboxylate.

Step B5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(piperidin-4-yl)benzamide,Salt with Hydrochloric Acid

tert-butyl4-[(5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzoyl)amino]piperidine-1-carboxylate(136 mg, 242 μmol) was dissolved in methanol and hydrogen chloride gaswas bubbled through the reaction for 20 min. The solvent was evaporatedto yield the desired product (98 mg, 82% yield).

Example 1652-(1-cyclohexylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2,5-difluoro-N-(pentan-3-yl)benzamide(Intermediate 87, 350 mg, 993 μmol) and 1-cyclopentylethanol (227 mg,1.99 mmol) were dissolved in DMF (20 ml). sodium hydride (95.3 mg, 50%in mineral oil, 1.99 mmol) was added carefully. The mixture was stirredat 80° C. overnight. The mixture was slowly poured into water (100 mL),extracted with ethyl acetate (3×20 ml) and the combined organicfractions were dried and concentrated. The product was purified usingcolumn chromatography (100 mg, 21% yield).

Example 1662-[(1-cyclopropylpropan-2-yl)oxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and1-cyclopropylpropan-2-ol.

Example 1672-(1-cyclopentylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and1-cyclopentylethanol.

Example 1682-(1-cyclopropylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and1-cyclopropylethanol.

Example 1694-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(1-phenylethoxy)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and1-phenylethanol.

Example 1704-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-[(3-ethylpentan-2-yl)oxy]-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and3-ethylpentan-2-ol.

Example 1714-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(4-methylpent-3-en-2-yl)oxy]-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and4-methylpent-3-en-2-ol.

Example 1724-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(pent-4-en-2-yloxy)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 andpent-4-en-2-ol.

Example 1732-(1-cyclobutylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide,Mixture of Stereoisomers

Synthesized analogous to Example 165 from Intermediate 87 and1-cyclobutylethanol.

Example 1745-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers Step A4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 165 from Intermediate 85 and(2S)-pentan-2-ol.

Step B5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide,Mixture of Stereoisomers

4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide(Intermediate from STEP A above, 50.0 mg, 98.3 μmol) was dissolved inmethanol (5 mL). 5 drops of hydrochloric acid (0.1N in water) wereadded. The mixture was stirred at room temperature until TLC showedcomplete conversion. Solid sodium carbonate was added and the mixturewas concentrated. The product was purified using column chromatographyto yield the desired product.

Example 1755-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers Step A4-{3-[1-(1-ethoxyethoxy)ethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers

Synthesized analogously to Example 165 from Intermediate 86 and2-pentanol.

Step B5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide,Mixture of Stereoisomers

The intermediate from STEP A was deprotected analogously to Example 174.

Example 176N-(2-chloro-6-fluorophenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 100 andIntermediate 7

LC-MS (Method A): R_(t)=1.26 min, MS (ESIpos): m/z=517 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.506 (2.67), 1.522 (2.71), 1.561(16.00), 2.084 (1.89), 2.518 (1.73), 2.523 (1.13), 3.455 (9.84), 5.302(0.49), 5.744 (4.69), 7.347 (0.62), 7.365 (0.49), 7.371 (0.47), 7.397(0.62), 7.411 (0.60), 7.418 (0.49), 7.429 (1.33), 7.433 (1.25), 7.693(0.45), 7.714 (0.84), 7.758 (0.94), 7.778 (0.51), 7.920 (1.14), 9.751(2.36).

Example 177N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 75 andIntermediate 6

LC-MS (Method A): R_(t)=1.13 min; MS (ESIpos): m/z=487 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.108 (0.72), 1.142 (0.94), 1.154(0.92), 1.172 (1.86), 1.190 (0.96), 1.264 (5.47), 1.282 (12.61), 1.300(5.66), 1.467 (0.69), 1.493 (6.60), 1.509 (6.63), 1.987 (3.14), 2.518(4.53), 2.523 (2.89), 3.771 (1.46), 3.789 (4.72), 3.807 (4.62), 3.824(1.41), 4.017 (0.74), 4.035 (0.72), 4.507 (5.34), 4.521 (5.44), 5.273(0.45), 5.289 (1.07), 5.305 (1.39), 5.321 (1.04), 5.336 (0.44), 5.759(16.00), 5.803 (1.28), 5.818 (2.94), 5.832 (1.24), 7.183 (1.98), 7.203(4.05), 7.224 (2.48), 7.360 (0.45), 7.376 (1.01), 7.396 (1.46), 7.412(0.81), 7.740 (7.72), 7.873 (3.56), 9.713 (6.55).

Example 178N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 100 andIntermediate 6

LC-MS (Method A): R_(t)=1.18 min; MS (ESIpos): m/z=503 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (0.89), 1.172 (1.78), 1.190(0.89), 1.265 (2.35), 1.284 (5.45), 1.301 (2.38), 1.500 (3.51), 1.516(3.51), 1.988 (3.13), 2.518 (4.45), 2.523 (2.95), 3.772 (0.62), 3.790(1.98), 3.808 (1.98), 3.825 (0.59), 4.017 (0.68), 4.035 (0.66), 4.509(1.90), 4.521 (1.96), 5.321 (0.50), 5.337 (0.64), 5.354 (0.48), 5.759(16.00), 5.821 (1.00), 7.346 (0.77), 7.369 (0.55), 7.395 (0.61), 7.409(0.66), 7.427 (1.60), 7.431 (1.55), 7.447 (0.44), 7.752 (2.99), 7.881(1.57), 9.772 (2.51).

Example 179N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide(Racemic)

Synthesized analogously to Example 92 from Intermediate 101 andIntermediate 7

LC-MS (Method A): R_(t)=1.22 min; MS (ESIneg): m/z=497 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.432 (2.27), 1.448 (2.25), 1.559(16.00), 2.083 (1.61), 2.518 (0.65), 2.522 (0.44), 3.455 (9.56), 5.746(4.46), 5.757 (0.55), 6.333 (0.47), 6.341 (0.47), 7.349 (0.66), 7.367(0.45), 7.372 (0.50), 7.399 (0.63), 7.413 (0.65), 7.419 (0.46), 7.434(1.29), 7.439 (1.20), 7.646 (0.68), 7.650 (0.68), 7.667 (0.77), 7.672(0.78), 7.907 (0.98), 7.928 (0.85), 7.949 (1.21), 7.952 (1.17), 9.595(2.01).

Example 180N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide(Racemic)

Synthesized analogously to Example 92 from Intermediate 101 andIntermediate 6

LC-MS (Method A): R_(t)=1.11 min; MS (ESIpos): m/z=485 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.108 (0.56), 1.142 (0.76), 1.154(1.29), 1.172 (2.55), 1.190 (1.31), 1.265 (5.67), 1.283 (13.21), 1.301(5.79), 1.429 (7.52), 1.444 (7.56), 1.467 (0.58), 1.988 (4.56), 2.518(5.65), 2.523 (3.66), 3.771 (1.49), 3.789 (4.82), 3.807 (4.76), 3.825(1.43), 4.017 (1.01), 4.035 (1.01), 4.508 (5.05), 4.521 (5.09), 4.921(0.82), 4.938 (0.82), 4.946 (0.80), 5.759 (16.00), 5.805 (1.17), 5.819(2.79), 5.833 (1.15), 6.188 (0.80), 6.196 (0.78), 6.325 (1.55), 6.333(1.57), 6.463 (0.74), 6.471 (0.76), 7.329 (0.92), 7.349 (2.21), 7.367(1.49), 7.372 (1.65), 7.379 (1.21), 7.393 (1.15), 7.399 (2.05), 7.413(2.09), 7.419 (1.55), 7.434 (4.36), 7.439 (4.04), 7.455 (1.31), 7.459(1.13), 7.692 (2.15), 7.697 (2.13), 7.713 (2.43), 7.717 (2.63), 7.897(7.06), 7.919 (2.75), 9.611 (6.13).

Example 181N-(2-chloro-6-fluorophenyl)-4-[4-cyclopropyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 and4-cyclopropyl-3-ethyl-1H-1,2,4-triazol-5(4H)-one

LC-MS (Method A): R_(t)=1.13 min, MS (ESIneg): m/z=531 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.835 (0.45), 0.946 (1.36), 0.965(5.14), 0.979 (5.73), 0.983 (4.95), 0.996 (2.64), 1.014 (1.27), 1.033(1.36), 1.041 (2.73), 1.051 (6.55), 1.059 (6.32), 1.072 (2.82), 1.081(1.32), 1.108 (1.14), 1.143 (1.50), 1.154 (5.00), 1.172 (9.05), 1.190(4.36), 1.232 (0.45), 1.433 (12.68), 1.449 (12.59), 1.467 (1.41), 1.484(0.45), 1.810 (0.64), 1.987 (16.00), 2.084 (14.41), 2.322 (1.91), 2.326(2.59), 2.331 (1.91), 2.522 (9.14), 2.664 (1.91), 2.668 (2.64), 2.673(1.91), 2.919 (0.95), 2.928 (1.95), 2.937 (2.68), 2.946 (3.64), 2.955(2.36), 2.963 (1.82), 2.973 (0.86), 3.469 (0.41), 4.000 (1.32), 4.017(3.86), 4.035 (3.82), 4.053 (1.27), 4.504 (7.45), 4.515 (7.55), 4.540(0.59), 5.299 (0.82), 5.316 (1.86), 5.331 (2.45), 5.347 (1.82), 5.363(0.77), 5.704 (2.55), 5.758 (13.95), 7.333 (1.27), 7.352 (2.86), 7.369(1.77), 7.376 (2.05), 7.385 (1.32), 7.405 (2.23), 7.419 (2.82), 7.430(5.86), 7.436 (6.50), 7.450 (1.64), 7.540 (4.86), 7.552 (4.18), 7.565(7.95), 10.065 (5.45).

Example 182N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 and5-(hydroxymethyl)-4-propyl-2,4-dihydro-3H-1,2,4-triazol-3-one

LC-MS (Method A): R_(t)=1.19 min; MS (ESIneg): m/z=533 [M−H]⁻

Example 183N-(2-chloro-6-fluorophenyl)-4-[4-cyclobutyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 and3-cyclobutyl-4-methyl-1H-1,2,4-triazol-5(4H)-one

LC-MS (Method A): R_(t)=1.22 min; MS (ESIneg): m/z=545 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (2.55), 1.172 (5.00), 1.190(2.52), 1.233 (0.40), 1.437 (15.95), 1.452 (16.00), 1.488 (0.67), 1.680(1.17), 1.700 (2.35), 1.706 (1.90), 1.726 (3.10), 1.746 (2.87), 1.770(3.42), 1.794 (2.37), 1.820 (0.65), 1.987 (9.07), 2.084 (3.07), 2.195(1.97), 2.215 (5.10), 2.222 (3.85), 2.236 (5.02), 2.256 (1.92), 2.326(1.45), 2.522 (5.72), 2.669 (1.45), 2.867 (1.10), 2.891 (3.70), 2.917(5.00), 2.945 (3.37), 2.970 (0.95), 3.566 (1.17), 4.000 (0.77), 4.017(2.22), 4.035 (2.22), 4.053 (0.70), 4.456 (9.97), 4.468 (10.05), 4.620(0.77), 4.642 (2.48), 4.664 (3.60), 4.686 (2.35), 4.708 (0.70), 5.325(1.05), 5.341 (2.40), 5.357 (3.05), 5.373 (2.27), 5.389 (0.92), 5.758(1.12), 5.770 (2.42), 5.784 (4.92), 5.797 (2.40), 7.336 (1.82), 7.355(3.95), 7.372 (2.48), 7.379 (2.87), 7.387 (2.05), 7.408 (3.50), 7.421(4.30), 7.433 (7.87), 7.438 (9.15), 7.453 (2.10), 7.548 (5.67), 7.573(6.80), 7.579 (6.15), 7.594 (5.15), 10.072 (8.92).

Example 184N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 71 and5-(hydroxymethyl)-4-(prop-2-en-1-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

LC-MS (Method A): R_(t)=1.16 min, MS (ESIpos): m/z=533 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.437 (5.63), 1.453 (5.64), 2.074(1.19), 2.518 (2.88), 2.523 (1.91), 4.396 (3.19), 4.409 (3.20), 4.443(3.19), 4.450 (3.16), 5.167 (1.56), 5.170 (1.63), 5.209 (1.78), 5.213(1.90), 5.223 (1.96), 5.227 (1.86), 5.249 (2.01), 5.253 (1.90), 5.350(0.84), 5.366 (1.08), 5.382 (0.78), 5.759 (16.00), 5.814 (1.01), 5.922(0.47), 5.936 (1.10), 5.948 (0.80), 5.961 (1.10), 5.978 (1.11), 5.991(0.73), 6.004 (0.90), 7.331 (0.51), 7.351 (1.21), 7.375 (0.92), 7.400(0.86), 7.429 (2.46), 7.433 (2.48), 7.448 (0.69), 7.555 (1.94), 7.580(2.02), 7.597 (1.39), 7.611 (1.35), 10.077 (2.09).

Example 185N-(2-chloro-6-fluorophenyl)-2-{[3,3-difluorobutan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluorobenzamide(Racemic)

Synthesized analogously to Example 92 from Intermediate 102 andIntermediate 6

LC-MS (Method A): R_(t)=1.13 min; MS (ESIneg): m/z=515 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.027 (1.52), 1.042 (2.23), 1.071(1.10), 1.138 (0.46), 1.237 (0.66), 1.255 (0.88), 1.265 (6.98), 1.282(16.00), 1.300 (7.08), 1.340 (10.09), 1.356 (9.96), 1.650 (6.02), 1.699(11.55), 1.748 (5.23), 2.074 (0.50), 2.084 (13.11), 2.518 (4.37), 2.522(2.95), 3.742 (0.44), 3.764 (1.86), 3.781 (6.02), 3.800 (5.85), 3.817(1.68), 4.478 (9.08), 4.492 (9.12), 4.896 (0.64), 4.920 (1.26), 4.936(1.26), 4.958 (0.60), 5.758 (1.36), 5.784 (2.79), 5.799 (6.54), 5.813(2.63), 7.336 (0.96), 7.341 (1.06), 7.361 (2.45), 7.378 (1.50), 7.384(1.90), 7.391 (1.30), 7.404 (1.06), 7.411 (2.33), 7.425 (2.61), 7.431(2.17), 7.438 (4.85), 7.444 (6.40), 7.458 (1.30), 7.464 (1.00), 7.531(3.51), 7.546 (3.49), 7.570 (3.81), 7.595 (3.65), 10.005 (8.52).

Example 1865-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 72 and5-(hydroxymethyl)-4-propyl-2,4-dihydro-3H-1,2,4-triazol-3-one

LC-MS (Method A): R_(t)=1.10 min; MS (ESIpos): m/z=528 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.900 (3.08), 0.918 (7.06), 0.936(3.35), 1.041 (0.70), 1.071 (0.70), 1.446 (5.15), 1.461 (5.15), 1.704(0.97), 1.722 (1.69), 1.741 (1.65), 1.760 (0.91), 2.084 (1.19), 2.185(0.45), 2.220 (12.10), 2.327 (0.88), 2.332 (0.65), 2.522 (3.15), 2.665(0.65), 2.669 (0.90), 2.673 (0.65), 3.687 (1.64), 3.706 (2.16), 3.724(1.51), 3.860 (16.00), 4.482 (2.52), 5.383 (0.79), 5.399 (1.02), 5.415(0.74), 5.810 (0.96), 6.933 (2.24), 6.946 (2.30), 7.566 (4.59), 7.582(2.15), 7.591 (2.60), 7.969 (2.69), 7.981 (2.55), 9.661 (3.01).

Example 187N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 103 andIntermediate 6

LC-MS (Method A): R_(t)=1.10 min, MS (ESIpos): m/z=521 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.108 (0.47), 1.142 (0.59), 1.154(0.98), 1.172 (1.98), 1.190 (1.02), 1.263 (2.33), 1.281 (5.28), 1.299(2.43), 1.432 (3.66), 1.448 (3.68), 1.988 (3.42), 2.518 (4.95), 2.523(3.16), 3.759 (0.60), 3.778 (2.11), 3.796 (1.97), 3.813 (0.66), 4.017(0.76), 4.035 (0.72), 4.470 (2.68), 4.484 (2.71), 4.952 (0.43), 5.759(16.00), 5.782 (0.72), 5.797 (1.61), 5.812 (0.69), 7.376 (0.60), 7.398(0.52), 7.452 (1.29), 7.479 (0.43), 7.501 (3.12), 10.397 (1.14).

Example 188N-(2-chloro-6-fluorophenyl)-3-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Synthesized analogously to Example 92 from Intermediate 103 andIntermediate 7

LC-MS (Method A): R_(t)=1.19 min; MS (ESIpos): m/z=535 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.431 (3.34), 1.448 (3.34), 1.520(16.00), 2.084 (1.85), 2.518 (1.20), 2.523 (0.78), 3.451 (9.75), 4.928(0.57), 4.944 (0.72), 4.959 (0.52), 5.745 (3.54), 7.380 (0.78), 7.396(0.48), 7.403 (0.63), 7.427 (0.69), 7.441 (0.80), 7.453 (1.49), 7.459(1.87), 7.473 (0.48), 7.479 (0.45), 7.487 (1.39), 7.495 (3.16), 10.371(1.44).

Example 189N-(6-chloro-2-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Can be synthesized analogously to Example 92 by first reactingIntermediate 68 with 6-chloro-2-fluoro-3-methoxyaniline followed bypalladium catalyzed coupling with Intermediate 6.

LC-MS (Method A): R_(t)=1.13 min; MS (ESIpos): m/z=551 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.961 (12.84), 0.978 (13.80), 1.173(0.77), 1.265 (4.22), 1.282 (9.85), 1.300 (4.30), 1.431 (5.99), 1.447(6.02), 1.988 (1.38), 2.518 (1.20), 2.523 (0.82), 2.796 (7.38), 2.805(0.47), 2.822 (0.85), 2.839 (1.05), 2.855 (0.78), 2.994 (7.78), 3.200(0.42), 3.765 (1.10), 3.783 (3.60), 3.801 (3.58), 3.819 (1.11), 3.882(16.00), 4.480 (5.32), 4.494 (5.37), 5.339 (0.91), 5.355 (1.18), 5.371(0.87), 5.790 (1.66), 5.805 (3.88), 5.819 (1.58), 7.180 (1.04), 7.202(2.17), 7.223 (1.37), 7.347 (1.87), 7.351 (1.85), 7.369 (1.45), 7.374(1.44), 7.542 (2.24), 7.567 (2.26), 7.584 (2.07), 7.598 (1.99), 10.062(4.94).

Example 190N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

N-(6-chloro-2-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Example 189, 160 mg, 290 μmol) was dissolved in DCM and cooled to −20°C. A solution of boron tribromide in DCM (1.2 ml, 1.0 M, 1.2 mmol) wasadded dropwise and the solution was stirred in an ice bath for 1 h. Thereaction was quenched by adding a water-methanol mixture (3:1) and themixture was extracted with DCM (2×). The combined organic phases werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. PrepHPLC yields the desired product (90.2 mg, 99% purity,58% yield).

LC-MS (Method A): R_(t)=1.02 min, MS (ESIpos): m/z=537 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.137 (0.46), 1.264 (4.41), 1.282(9.64), 1.300 (4.48), 1.436 (7.00), 1.451 (7.02), 2.084 (16.00), 2.327(0.54), 2.669 (0.55), 3.764 (1.26), 3.782 (3.87), 3.801 (3.82), 3.818(1.27), 4.486 (5.79), 5.325 (0.46), 5.340 (1.08), 5.357 (1.39), 5.373(1.03), 5.388 (0.42), 5.758 (5.10), 5.804 (0.83), 6.927 (1.23), 6.949(2.57), 6.971 (1.47), 7.172 (2.08), 7.191 (1.74), 7.536 (2.58), 7.561(2.60), 7.581 (2.48), 7.596 (2.45), 9.974 (4.33).

Example 1913-chloro-4-(4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamido)-5-fluorophenyl2,2-dimethylpropanoate

Can be synthesized analogously to Example 92 by first reactingIntermediate 68 with 4-amino-3-chloro-5-fluorophenyl pivalate followedby palladium catalyzed coupling with Intermediate 6.

LC-MS (Method A): R_(t)=1.37 min; MS (ESIpos): m/z=621 [M+H]⁺

Example 192N-(2-chloro-6-fluoro-4-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

To a solution of3-chloro-4-(4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamido)-5-fluorophenyl2,2-dimethylpropanoate (Example 191, 200 mg, 322 μmol) in dioxane (2 mL)was added water (0.5 mL) and lithium hydroxide (23.1 mg, 966 μmol). Themixture was stirred at room temperature for 1 h. Water was added and themixture was extracted with ethyl acetate (3×). The combined organicphases were washed with brine, dried over sodium sulfate, filtered, andconcentrated. PrepHPLC followed by trituration in ethanol/water yieldsthe desired product (67.4 mg, 98% purity, 38% yield).

LC-MS (Method A): R_(t)=1.01 min; MS (ESIpos): m/z=537 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.052 (0.66), 1.201 (2.11), 1.261(7.28), 1.279 (16.00), 1.297 (7.40), 1.311 (1.14), 1.382 (0.51), 1.425(12.85), 1.440 (13.00), 1.514 (1.37), 2.084 (2.09), 2.322 (1.09), 2.326(1.48), 2.668 (1.48), 2.673 (1.12), 3.762 (2.03), 3.779 (6.18), 3.797(6.13), 3.815 (1.96), 4.482 (8.04), 5.307 (0.79), 5.323 (1.96), 5.340(2.57), 5.356 (1.93), 5.371 (0.81), 5.801 (1.42), 6.677 (2.95), 6.683(3.31), 6.705 (2.85), 6.710 (3.26), 6.788 (5.27), 6.794 (4.02), 7.507(5.88), 7.531 (5.80), 7.563 (4.99), 7.578 (5.09), 9.723 (8.75).

Example 193N-(2-chloro-6-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Can be synthesized analogously to Example 92 by first reactingIntermediate 68 with 2-chloro-6-fluoro-3-methoxyaniline followed bypalladium catalyzed coupling with Intermediate 6.

LC-MS (Method A): R_(t)=1.13 min, MS (ESIpos): m/z=551 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.961 (1.41), 0.977 (1.27), 1.154(1.22), 1.172 (2.40), 1.190 (1.13), 1.237 (0.47), 1.263 (3.99), 1.281(9.54), 1.299 (4.04), 1.428 (5.25), 1.444 (5.28), 1.988 (4.34), 2.518(2.19), 2.523 (1.46), 2.795 (0.69), 2.994 (0.71), 3.764 (1.02), 3.781(3.35), 3.800 (3.26), 3.817 (0.98), 3.875 (16.00), 4.017 (0.98), 4.035(0.97), 4.479 (3.16), 4.491 (3.12), 5.338 (0.76), 5.354 (1.02), 5.370(0.74), 5.797 (0.66), 5.811 (1.29), 7.138 (0.63), 7.149 (0.69), 7.161(0.86), 7.173 (0.80), 7.292 (0.96), 7.315 (1.57), 7.338 (0.73), 7.544(1.68), 7.568 (1.97), 7.575 (1.46), 7.591 (1.23), 10.057 (2.24).

Example 194N-(2-chloro-6-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

Can be synthesized analogously to Example 190 from Example 193.

LC-MS (Method A): R_(t)=0.96 min; MS (ESIpos): m/z=537 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (0.80), 1.172 (1.66), 1.190(0.83), 1.263 (2.28), 1.281 (5.30), 1.299 (2.35), 1.431 (3.30), 1.447(3.32), 1.988 (2.93), 2.084 (16.00), 2.518 (3.08), 2.523 (2.04), 3.566(0.42), 3.764 (0.60), 3.782 (1.96), 3.799 (1.93), 3.817 (0.60), 4.017(0.66), 4.035 (0.65), 4.485 (3.84), 5.337 (0.49), 5.353 (0.65), 5.370(0.49), 6.918 (0.56), 6.930 (0.61), 6.941 (0.79), 6.952 (0.74), 7.102(0.69), 7.125 (1.22), 7.148 (0.55), 7.538 (1.21), 7.563 (1.24), 7.576(1.19), 7.591 (1.16), 9.944 (1.00).

Example 1952-[(1S)-1-cyclohexylethoxy]-N-(1,4-dimethyl-1H-pyrazol-3-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzamide

Synthesized analogously to Example 1 from Intermediate 104 and1,4-dimethyl-1H-pyrazol-3-amine

LC-MS (Method A): R_(t)=1.30 min; MS (ESIpos): m/z=485 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.042 (0.64), 1.064 (0.96), 1.096(0.96), 1.132 (1.92), 1.146 (1.92), 1.156 (1.92), 1.173 (1.60), 1.188(5.12), 1.207 (9.60), 1.226 (6.40), 1.229 (7.36), 1.245 (6.40), 1.600(1.28), 1.615 (0.96), 1.688 (1.92), 1.850 (0.64), 1.881 (0.64), 1.903(1.28), 1.913 (12.48), 2.322 (1.28), 2.326 (1.60), 2.331 (1.28), 2.517(7.36), 2.522 (4.80), 2.539 (16.00), 2.623 (1.60), 2.642 (4.16), 2.660(4.48), 2.668 (1.92), 2.673 (1.28), 2.678 (1.60), 3.197 (2.56), 3.216(16.00), 3.242 (0.32), 3.252 (0.32), 3.280 (0.64), 3.327 (2.24), 3.342(3.84), 3.422 (6.08), 3.435 (3.52), 3.450 (1.92), 3.490 (0.96), 3.500(0.64), 3.526 (0.32), 3.718 (15.36), 4.362 (0.64), 4.376 (1.28), 4.391(0.64), 7.308 (1.92), 7.324 (1.92), 7.440 (3.84), 7.595 (2.56), 7.622(2.56), 9.774 (3.20).

Example 1962-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[1-(4-fluorophenyl)cyclopropyl]benzamide

Synthesized analogously to Example 1 from Intermediate 104 and1-(4-fluorophenyl)cyclopropan-1-amine

LC-MS (Method A): R_(t)=1.49 min, MS (ESIpos): m/z=525 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.003 (0.45), 1.010 (0.43), 1.072(0.57), 1.104 (0.81), 1.133 (0.85), 1.164 (0.70), 1.171 (0.61), 1.182(4.42), 1.196 (6.57), 1.201 (11.09), 1.211 (5.89), 1.220 (4.92), 1.228(1.07), 1.242 (5.48), 1.252 (1.93), 1.261 (0.88), 1.612 (0.54), 1.650(0.61), 1.690 (1.30), 1.715 (0.71), 1.817 (0.44), 1.847 (0.41), 2.084(1.44), 2.322 (0.53), 2.327 (0.72), 2.332 (0.53), 2.518 (2.90), 2.523(1.88), 2.616 (1.12), 2.635 (3.92), 2.653 (3.62), 2.664 (0.63), 2.669(0.95), 2.672 (1.43), 3.209 (16.00), 4.301 (0.64), 4.316 (0.94), 4.331(0.63), 7.074 (1.86), 7.080 (0.63), 7.091 (0.72), 7.097 (3.94), 7.102(0.72), 7.114 (0.63), 7.119 (2.25), 7.242 (1.71), 7.257 (1.71), 7.273(2.18), 7.278 (0.85), 7.286 (2.33), 7.295 (1.95), 7.303 (0.73), 7.309(1.67), 7.480 (2.49), 7.506 (2.49), 8.852 (2.63).

Example 1972-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(oxan-4-yl)benzamide

Synthesized analogously to Example 1 from Intermediate 104 and4-aminotetrahydropyran

LC-MS (Method A): R_(t)=1.29 min; MS (ESIpos): m/z=275 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.016 (0.43), 1.023 (0.43), 1.045(0.55), 1.053 (0.54), 1.076 (0.42), 1.099 (0.62), 1.129 (0.81), 1.137(1.11), 1.163 (0.99), 1.182 (4.70), 1.194 (1.41), 1.200 (9.75), 1.213(6.81), 1.219 (5.97), 1.229 (6.48), 1.446 (0.76), 1.456 (0.88), 1.477(0.97), 1.488 (0.85), 1.505 (0.49), 1.516 (0.41), 1.609 (0.51), 1.631(0.68), 1.662 (0.56), 1.683 (0.60), 1.714 (1.70), 1.745 (0.86), 1.830(1.10), 1.836 (1.12), 1.850 (1.16), 1.861 (1.06), 2.323 (0.49), 2.327(0.69), 2.331 (0.49), 2.518 (3.72), 2.523 (2.46), 2.617 (1.25), 2.636(3.98), 2.654 (3.90), 2.665 (0.65), 2.669 (0.90), 2.673 (1.57), 3.197(0.63), 3.210 (16.00), 3.386 (0.85), 3.391 (1.05), 3.414 (1.85), 3.419(1.80), 3.443 (1.09), 3.449 (0.86), 3.839 (1.27), 3.868 (1.11), 3.989(0.50), 3.999 (0.41), 4.008 (0.50), 4.341 (0.72), 4.356 (1.09), 4.372(0.72), 7.280 (1.88), 7.296 (1.88), 7.591 (2.59), 7.618 (2.56), 8.113(1.16), 8.132 (1.16).

Example 1982-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-phenylbutan-2-yl)benzamide

Synthesized analogously to Example 1 from Intermediate 104 and1-phenylbutane-2-amine

LC-MS (Method A): R_(t)=1.61 min; MS (ESIpos): m/z=523 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.889 (1.26), 0.898 (1.61), 0.908(3.07), 0.917 (3.21), 0.926 (1.61), 0.935 (1.61), 1.015 (0.49), 1.047(0.56), 1.076 (0.63), 1.101 (0.70), 1.137 (1.26), 1.145 (3.98), 1.147(4.33), 1.160 (3.98), 1.163 (4.12), 1.180 (4.26), 1.188 (0.70), 1.198(8.87), 1.217 (4.12), 1.234 (0.63), 1.356 (1.26), 1.366 (0.63), 1.385(0.63), 1.399 (0.42), 1.570 (0.42), 1.588 (0.98), 1.599 (1.19), 1.618(0.98), 1.634 (0.91), 1.667 (0.91), 1.754 (0.49), 2.074 (0.56), 2.084(8.52), 2.318 (0.49), 2.322 (1.12), 2.327 (1.68), 2.332 (1.19), 2.336(0.56), 2.518 (6.50), 2.523 (4.40), 2.539 (0.49), 2.615 (1.19), 2.634(3.91), 2.653 (3.84), 2.660 (0.70), 2.665 (1.33), 2.669 (2.03), 2.678(0.63), 2.774 (0.49), 2.794 (0.70), 2.817 (0.91), 2.833 (0.91), 3.209(16.00), 3.377 (0.42), 3.382 (0.42), 4.335 (0.56), 4.342 (0.42), 4.350(0.42), 4.357 (0.56), 5.758 (0.98), 7.179 (2.03), 7.197 (2.93), 7.199(3.00), 7.219 (0.49), 7.222 (0.56), 7.256 (1.33), 7.273 (2.45), 7.280(1.47), 7.288 (2.38), 7.292 (0.98), 7.305 (0.49), 7.476 (1.33), 7.503(1.26), 7.570 (1.26), 7.597 (1.19), 7.926 (0.56), 7.948 (0.56), 7.969(0.63), 7.990 (0.56).

Example 1992-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[3-(methanesulfonyl)phenyl]benzamide

Synthesized analogously to Example 1 from Intermediate 104 and3-(methanesulfonyl)aniline

LC-MS (Method A): R_(t)=1.33 min, MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.983 (0.54), 1.002 (0.60), 1.106(0.80), 1.137 (2.21), 1.171 (1.14), 1.187 (1.27), 1.195 (3.41), 1.204(3.41), 1.213 (7.16), 1.220 (3.55), 1.232 (3.48), 1.580 (0.60), 1.623(1.07), 1.646 (0.94), 1.905 (1.54), 2.085 (5.76), 2.116 (0.60), 2.318(1.14), 2.323 (2.61), 2.327 (3.82), 2.332 (2.81), 2.336 (1.21), 2.518(16.00), 2.523 (10.85), 2.539 (0.94), 2.631 (0.94), 2.649 (2.74), 2.660(1.34), 2.665 (3.01), 2.668 (5.89), 2.673 (2.95), 2.678 (1.27), 2.687(0.74), 3.211 (8.70), 3.223 (11.05), 4.308 (0.40), 4.323 (0.54), 5.759(6.36), 7.305 (1.00), 7.320 (1.07), 7.606 (1.61), 7.632 (1.74), 7.651(1.07), 7.660 (0.94), 7.667 (2.21), 7.900 (0.54), 7.916 (0.60), 8.378(1.21), 10.554 (1.87).

Example 2002-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-methyl-1H-pyrazol-5-yl)benzamide

Synthesized analogously to Example 1 from Intermediate 104 and1-methyl-1H-pyrazol-5-amine

LC-MS (Method A): R_(t)=1.23 min; MS (ESIpos): m/z=471 [M+H]⁺

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.842 (1.00), 0.849 (1.20),0.858 (0.87), 0.865 (0.84), 1.083 (0.45), 1.090 (0.47), 1.126 (0.50),1.132 (0.58), 1.164 (0.88), 1.194 (0.81), 1.220 (0.68), 1.226 (0.75),1.234 (0.57), 1.250 (0.76), 1.260 (1.77), 1.280 (0.59), 1.286 (0.54),1.354 (3.55), 1.373 (8.40), 1.389 (6.00), 1.392 (4.65), 1.404 (5.47),1.700 (0.69), 1.708 (0.62), 1.715 (0.55), 1.737 (0.66), 1.784 (1.02),1.815 (0.58), 2.635 (1.14), 2.654 (3.51), 2.673 (3.39), 2.692 (1.02),3.338 (16.00), 3.830 (13.28), 4.435 (0.57), 4.450 (0.83), 4.466 (0.54),6.418 (1.31), 6.422 (1.37), 7.377 (1.49), 7.392 (1.47), 7.481 (1.63),7.487 (1.64), 8.116 (2.06), 8.145 (2.06), 9.850 (1.24).

Example 2012-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(methylsulfanyl)phenyl]benzamide

Synthesized analogously to Example 1 from Intermediate 104 and4-(methylsulfanyl)aniline

LC-MS (Method A): R_(t)=1.57 min; MS (ESIpos): m/z=513 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.000 (0.48), 1.030 (0.64), 1.060(0.42), 1.113 (0.71), 1.137 (1.00), 1.169 (0.58), 1.192 (3.77), 1.210(10.78), 1.225 (4.80), 1.229 (4.31), 1.356 (0.97), 1.572 (0.55), 1.601(0.71), 1.641 (1.29), 1.666 (1.13), 2.323 (0.68), 2.327 (0.97), 2.332(0.71), 2.463 (16.00), 2.518 (3.80), 2.523 (2.58), 2.627 (0.97), 2.646(3.19), 2.664 (3.61), 2.669 (1.26), 2.673 (0.80), 2.678 (0.42), 2.683(0.90), 3.200 (0.45), 3.219 (12.17), 4.321 (0.52), 4.335 (0.71), 4.350(0.52), 7.268 (2.80), 7.273 (0.90), 7.285 (1.00), 7.289 (3.06), 7.297(1.67), 7.312 (1.42), 7.601 (1.96), 7.627 (2.19), 7.632 (3.25), 7.637(1.00), 7.649 (0.93), 7.654 (2.67), 10.172 (2.22).

Example 2024-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylpyridin-3-yl)-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and4-methylpyridin-3-amine

LC-MS (Method B): R_(t)=1.15 min, MS (ESIneg): m/z=474 [M−H]⁻

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.261 (0.50), 1.282 (2.71),1.324 (3.60), 1.343 (8.69), 1.362 (3.78), 1.809 (5.48), 1.825 (5.33),2.180 (9.18), 2.598 (1.22), 2.617 (3.66), 2.635 (3.56), 2.654 (1.02),3.306 (16.00), 5.621 (1.03), 5.637 (1.02), 7.155 (0.85), 7.167 (0.88),7.328 (0.86), 7.336 (0.49), 7.339 (0.53), 7.345 (1.22), 7.350 (0.94),7.353 (1.18), 7.359 (0.69), 7.373 (3.89), 7.386 (2.40), 7.391 (3.55),7.395 (2.50), 7.411 (0.88), 7.416 (0.53), 8.129 (2.06), 8.159 (2.01),8.336 (0.79), 8.349 (0.77), 9.083 (1.21), 9.684 (1.13).

Example 2034-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylquinolin-5-yl)-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and2-methylquinolin-5-amine

LC-MS (Method B): R_(t)=1.23 min; MS (ESIpos): m/z=526 [M+H]⁺

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.261 (0.72), 1.282 (9.22),1.334 (3.71), 1.353 (8.70), 1.371 (3.66), 1.616 (0.96), 1.822 (4.87),1.838 (4.90), 2.608 (1.20), 2.626 (3.60), 2.645 (3.53), 2.664 (0.97),2.752 (10.93), 3.281 (0.44), 3.316 (16.00), 3.927 (0.43), 5.672 (0.94),5.688 (0.93), 7.174 (2.10), 7.196 (2.24), 7.300 (0.58), 7.303 (0.65),7.309 (0.51), 7.312 (0.97), 7.317 (3.26), 7.322 (1.70), 7.328 (0.48),7.332 (0.89), 7.336 (2.20), 7.343 (0.44), 7.347 (0.40), 7.351 (0.70),7.359 (0.57), 7.403 (1.85), 7.407 (1.85), 7.419 (2.23), 7.427 (1.27),7.434 (1.65), 7.716 (0.83), 7.736 (1.31), 7.756 (1.16), 7.899 (1.02),7.920 (0.81), 8.053 (1.31), 8.075 (1.25), 8.105 (1.18), 8.123 (1.07),8.175 (1.91), 8.204 (1.86), 10.346 (1.23).

Example 204N-[3-(cyclopropylcarbamoyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and3-amino-N-cyclopropylbenzamide

LC-MS (Method B): R_(t)=1.19 min; MS (ESIneg): m/z=543 [M−H]⁻

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.652 (1.16), 0.656 (1.24),0.661 (1.25), 0.665 (1.26), 0.668 (1.11), 0.679 (0.50), 0.870 (0.52),0.884 (1.22), 0.887 (1.58), 0.901 (1.52), 0.905 (1.17), 1.040 (1.19),1.261 (0.98), 1.282 (16.00), 1.299 (0.75), 1.325 (3.48), 1.343 (7.54),1.362 (3.65), 1.403 (0.53), 1.421 (1.10), 1.440 (0.55), 1.606 (5.30),1.869 (4.89), 1.884 (5.00), 2.598 (1.11), 2.616 (3.31), 2.635 (3.30),2.654 (0.92), 2.900 (0.47), 2.910 (0.62), 2.918 (0.61), 2.928 (0.46),3.306 (14.37), 5.589 (1.02), 5.605 (1.02), 6.347 (0.59), 7.334 (1.66),7.348 (1.80), 7.363 (0.83), 7.366 (0.69), 7.370 (1.15), 7.374 (0.61),7.380 (1.19), 7.385 (0.92), 7.390 (2.02), 7.392 (1.30), 7.398 (0.69),7.412 (2.85), 7.429 (4.30), 7.433 (2.96), 7.449 (0.79), 7.454 (0.47),7.556 (1.69), 7.558 (1.59), 7.561 (1.20), 7.575 (1.36), 7.578 (1.18),7.581 (0.88), 8.058 (1.02), 8.062 (1.75), 8.067 (1.00), 8.095 (1.95),8.124 (1.93), 10.254 (1.30).

Example 205N-[2-(difluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and2-(difluoromethyl)aniline-hydrogen chloride

LC-MS (Method B): R_(t)=1.35 min, MS (ESIneg): m/z=509 [M−H]⁻

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.135 (0.77), 1.041 (0.45),1.263 (1.40), 1.311 (3.60), 1.330 (7.42), 1.349 (3.76), 1.577 (0.78),1.767 (3.52), 1.782 (3.53), 2.581 (1.13), 2.599 (3.53), 2.618 (3.26),2.626 (0.46), 2.636 (0.92), 3.290 (16.00), 5.554 (0.84), 5.570 (0.84),6.608 (0.76), 6.746 (1.54), 6.884 (0.72), 7.279 (0.53), 7.285 (1.67),7.289 (0.48), 7.299 (2.17), 7.310 (0.66), 7.314 (1.71), 7.318 (1.44),7.336 (1.56), 7.341 (0.69), 7.352 (0.91), 7.356 (2.61), 7.368 (0.42),7.374 (1.56), 7.376 (1.16), 7.386 (2.08), 7.390 (2.32), 7.407 (1.08),7.411 (0.73), 7.541 (0.46), 7.557 (1.54), 7.577 (1.15), 7.986 (0.81),8.007 (0.78), 8.086 (1.83), 8.116 (1.83), 9.979 (0.92).

Example 2064-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(6-methyl-1H-indazol-5-yl)-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and6-methyl-1H-indazol-5-amine

LC-MS (Method B): R_(t)=1.14 min; MS (ESIneg): m/z=513 [M−H]⁻

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.041 (1.62), 1.195 (1.34),1.262 (0.55), 1.283 (4.92), 1.300 (0.99), 1.327 (3.83), 1.345 (8.33),1.364 (4.01), 1.418 (0.64), 1.768 (5.08), 1.784 (5.22), 2.308 (8.16),2.599 (1.22), 2.617 (3.57), 2.636 (3.52), 2.655 (0.98), 3.316 (16.00),5.485 (1.10), 5.502 (1.08), 7.213 (1.73), 7.228 (2.49), 7.231 (2.30),7.312 (0.75), 7.315 (0.56), 7.321 (0.74), 7.328 (0.96), 7.333 (0.79),7.340 (0.85), 7.343 (0.77), 7.347 (0.63), 7.355 (0.56), 7.360 (3.26),7.370 (3.42), 7.376 (6.16), 7.391 (0.51), 7.993 (2.18), 8.128 (2.27),8.157 (2.22), 8.361 (3.27), 9.608 (1.58).

Example 207N-(1-cyanobutan-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide

Synthesized analogously to Example 1 from Intermediate 43 and3-aminopentanenitrile

LC-MS (Method B): R_(t)=1.19 min; MS (ESIneg): m/z=465 [M−H]⁻

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.927 (2.50), 0.946 (5.97),0.964 (2.76), 1.034 (2.24), 1.041 (0.65), 1.053 (5.33), 1.071 (2.46),1.262 (0.99), 1.282 (12.40), 1.300 (0.45), 1.307 (3.25), 1.312 (3.77),1.325 (7.39), 1.331 (8.31), 1.344 (3.52), 1.349 (3.81), 1.580 (3.66),1.609 (0.50), 1.627 (0.42), 1.644 (0.61), 1.666 (0.63), 1.684 (0.54),1.697 (0.66), 1.715 (0.84), 1.731 (1.10), 1.750 (0.91), 1.762 (0.60),1.771 (0.61), 1.778 (0.72), 1.795 (5.35), 1.801 (6.05), 1.811 (5.25),1.818 (6.05), 2.576 (1.08), 2.584 (1.25), 2.595 (3.24), 2.603 (4.33),2.607 (1.36), 2.614 (3.48), 2.622 (3.64), 2.633 (0.99), 2.641 (1.30),2.643 (1.39), 2.649 (1.32), 2.652 (1.33), 2.658 (1.10), 2.895 (1.00),2.908 (1.06), 2.938 (1.34), 2.952 (1.49), 2.981 (0.93), 2.994 (0.89),3.285 (13.98), 3.291 (16.00), 4.209 (0.46), 4.223 (0.42), 4.230 (0.40),4.243 (0.43), 5.512 (0.61), 5.528 (2.02), 5.544 (1.99), 5.560 (0.60),7.241 (1.68), 7.254 (3.00), 7.312 (1.05), 7.317 (0.49), 7.326 (0.63),7.329 (1.27), 7.333 (0.71), 7.338 (0.78), 7.347 (0.71), 7.354 (0.99),7.360 (1.71), 7.379 (3.02), 7.392 (0.92), 7.397 (4.39), 7.408 (3.41),7.414 (7.32), 7.419 (2.94), 7.429 (0.73), 7.436 (1.37), 7.440 (0.86),8.004 (2.00), 8.023 (2.30), 8.034 (2.02), 8.053 (2.26), 8.339 (0.64),8.358 (0.64), 8.397 (0.57), 8.415 (0.56).

Example 2082-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)benzamide

Synthesized analogously to Example 73 from Intermediate 93 and2-fluoro-6-methylaniline

LC-MS (Method B): R_(t)=1.24 min, MS (ESIpos): m/z=474 [M+H]⁺

¹H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.133 (1.69), 1.262 (3.69),1.282 (0.47), 1.351 (3.78), 1.370 (8.52), 1.389 (3.93), 1.477 (0.70),1.486 (5.97), 1.492 (1.03), 1.501 (5.93), 1.620 (0.42), 2.123 (1.10),2.315 (1.17), 2.325 (9.23), 2.631 (1.28), 2.649 (3.87), 2.668 (3.85),2.687 (1.15), 3.333 (16.00), 6.958 (0.49), 6.979 (0.93), 7.002 (0.54),7.046 (0.73), 7.065 (1.07), 7.134 (0.56), 7.148 (0.59), 7.154 (0.78),7.167 (0.77), 7.352 (0.89), 7.366 (0.92), 7.961 (0.95), 7.989 (0.94).

Example 2092-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(S-methanesulfonimidoyl)phenyl]benzamide(Mixture of Stereoisomers)

Following a procedure by Tota et al. (Chem. Commun. 2017, 53, 348-351)2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(methylsulfanyl)phenyl]benzamide(Example 201, 38.0 mg, 74.1 μmol) was dissolved in methanol (500 μl).Ammonium carbamate (17.4 mg, 222 μmol) was added followed by(diacetoxyiodo)benzene (47.8 mg, 148 μmol). The mixture was stirred atroom temperature for 2 h. The reaction mixture was filtered and purifiedby prepHPLC to yield the desired product 26.6 mg (95% purity, 63%yield).

LC-MS (Method A): R_(t)=1.15 min, MS (ESIpos): m/z=544 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.982 (0.68), 1.011 (0.89), 1.042(0.56), 1.101 (0.84), 1.125 (1.00), 1.137 (1.03), 1.165 (0.49), 1.174(0.44), 1.194 (4.81), 1.201 (4.65), 1.213 (11.47), 1.231 (4.60), 1.448(0.51), 1.463 (0.51), 1.522 (2.52), 1.558 (0.72), 1.586 (0.89), 1.622(1.73), 1.650 (1.47), 1.770 (0.49), 1.800 (0.47), 2.084 (1.26), 2.323(0.63), 2.327 (0.91), 2.331 (0.65), 2.518 (3.20), 2.523 (2.22), 2.631(1.19), 2.649 (3.99), 2.668 (4.27), 2.673 (0.89), 2.686 (1.12), 3.043(9.44), 3.223 (16.00), 3.452 (1.78), 4.146 (2.20), 4.316 (0.61), 4.330(0.84), 4.344 (0.58), 5.781 (0.54), 7.310 (1.66), 7.325 (1.66), 7.608(2.52), 7.633 (2.41), 7.855 (1.31), 7.877 (3.60), 7.899 (5.21), 7.916(0.72), 7.922 (1.66), 10.538 (2.94).

Example 210N-(2,6-difluorophenyl)-4-[4-ethyl-3-(S-methanesulfonimidoyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Mixture of Stereoisomers)

Synthesized analogously to Example 209 from Example 115

LC-MS (Method A): R_(t)=1.14 min, MS (ESIpos): m/z=552 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.137 (0.61), 1.233 (0.57), 1.296(4.10), 1.314 (9.02), 1.332 (4.06), 1.441 (6.01), 1.456 (6.01), 1.522(1.83), 2.085 (4.55), 2.337 (0.77), 2.518 (8.93), 2.523 (6.09), 2.674(1.66), 2.678 (0.77), 3.372 (16.00), 3.452 (1.30), 3.957 (0.41), 3.975(0.89), 3.992 (2.11), 4.009 (2.92), 4.027 (2.07), 4.045 (0.89), 4.063(0.41), 5.275 (0.41), 5.292 (0.97), 5.307 (1.30), 5.323 (0.93), 5.637(2.96), 5.760 (3.70), 7.195 (1.66), 7.215 (3.41), 7.235 (2.11), 7.391(0.81), 7.410 (0.97), 7.426 (0.69), 7.636 (2.80), 7.647 (1.99), 7.660(4.22), 10.061 (4.02).

Example 2111-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Step A

N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Example 178, 160 mg, 318 μmol) was dissolved in dichloromethane (2 mL).Dess-Martin-periodinane(1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 202 mg,477 μmol) was added and the mixture was stirred overnight at roomtemperature. The mixture was diluted with water and extracted with DCM(3×). The combined organic phases were washed with sat. sodiumbicarbonate solution and brine, dried over sodium sulfate, filtered andconcentrated to yield crudeN-(2-chloro-6-fluorophenyl)-4-(4-ethyl-3-formyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(157 mg, 99% yield, LC-MS (Method B): R_(t)=1.27 min; MS (ESIpos):m/z=501 [M+H]⁺).

Step B

The aldehyde from STEP A (157 mg, 313 μmol) was dissolved intert-butanol (6.6 mL) and 2-methyl-2-butene (330 μl). A solution ofsodium chlorite (319 mg, 80% purity, 2.82 mmol) and sodium dihydrogenphosphate dehydrate (342 mg, 2.19 mmol) in water (2.5 mL) was addeddropwise at room temperature. The mixture was stirred at roomtemperature for 2 h. The mixture was concentrated, diluted with waterand extracted with ethyl acetate (3×). The combined organic phases weredried over sodium sulfate, filtered, and concentrated. The crude productwas purified using prepHPLC to yield the desired product (60.0 mg, 95%purity, 35% yield).

LC-MS (Method A): R_(t)=1.08 min; MS (ESIpos): m/z=517 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (1.43), 1.172 (2.86), 1.190(1.39), 1.246 (2.61), 1.264 (6.08), 1.282 (2.63), 1.501 (4.03), 1.517(4.04), 1.988 (4.92), 2.518 (1.93), 2.523 (1.26), 2.539 (16.00), 3.340(1.03), 3.990 (0.64), 4.000 (0.76), 4.008 (2.08), 4.017 (1.65), 4.026(2.06), 4.035 (1.50), 4.043 (0.64), 4.053 (0.47), 5.328 (0.58), 5.344(0.75), 5.360 (0.55), 7.351 (0.89), 7.369 (0.56), 7.375 (0.66), 7.381(0.51), 7.395 (0.43), 7.402 (0.83), 7.415 (0.91), 7.421 (0.75), 7.431(1.88), 7.436 (1.99), 7.451 (0.52), 7.456 (0.41), 7.758 (2.11), 7.763(2.37), 7.907 (1.79), 9.851 (3.81).

Example 2121-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Synthesized analogously to Example 211 from Example 121

LC-MS (Method A): R_(t)=1.06 min; MS (ESIpos): m/z=535 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.248 (6.93), 1.266 (15.69), 1.284(7.36), 1.444 (11.48), 1.460 (11.69), 1.907 (1.32), 2.084 (16.00), 2.323(0.78), 2.327 (1.13), 2.331 (0.87), 2.522 (5.96), 2.665 (0.87), 2.669(1.22), 2.673 (0.93), 3.337 (2.33), 3.987 (1.86), 4.005 (5.69), 4.023(5.65), 4.040 (1.86), 5.315 (0.70), 5.332 (1.73), 5.347 (2.29), 5.363(1.69), 5.379 (0.72), 5.759 (0.45), 7.342 (1.22), 7.361 (2.76), 7.377(1.69), 7.384 (2.12), 7.393 (1.40), 7.413 (2.58), 7.426 (3.09), 7.437(5.77), 7.443 (7.13), 7.457 (1.55), 7.591 (4.49), 7.615 (4.47), 7.665(3.98), 7.679 (4.00), 10.126 (9.01).

Example 2131-(4-[(2,6-difluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Synthesized analogously to Example 211 from Example 177 LC-MS (MethodA): R_(t)=1.04 min; MS (ESIpos): m/z=501 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.107 (0.58), 1.149 (0.89), 1.154(0.46), 1.172 (0.74), 1.180 (0.81), 1.190 (0.43), 1.228 (7.05), 1.246(16.00), 1.264 (7.09), 1.389 (0.62), 1.406 (0.66), 1.495 (8.79), 1.511(8.76), 1.907 (1.24), 1.987 (1.12), 2.084 (1.24), 2.332 (1.59), 2.336(0.70), 2.518 (8.33), 2.523 (5.54), 2.539 (1.08), 2.678 (0.70), 3.992(1.82), 4.010 (5.69), 4.027 (5.58), 4.045 (1.70), 5.278 (0.62), 5.294(1.43), 5.310 (1.86), 5.325 (1.39), 5.341 (0.54), 5.758 (1.55), 6.971(1.32), 7.098 (1.67), 7.186 (2.67), 7.206 (5.50), 7.226 (4.61), 7.362(0.62), 7.378 (1.36), 7.399 (1.94), 7.415 (1.08), 7.437 (0.43), 7.727(0.97), 7.749 (7.32), 7.776 (0.81), 7.895 (4.46), 8.136 (0.43), 9.770(10.11).

Example 2144-ethyl-1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Synthesized analogously to Example 211 from Example 128 LC-MS (MethodA): R_(t)=1.04 min; MS (ESIpos): m/z=515 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.150 (0.58), 1.180 (0.56), 1.244(0.98), 1.262 (2.20), 1.280 (0.97), 1.390 (0.41), 1.406 (0.42), 1.437(1.78), 1.453 (1.78), 1.988 (0.44), 2.278 (4.12), 2.518 (1.26), 2.523(0.86), 2.539 (16.00), 4.006 (0.80), 4.024 (0.79), 5.758 (2.61), 7.120(0.55), 7.125 (0.57), 7.137 (0.65), 7.250 (0.41), 7.600 (0.92), 7.624(0.89), 7.644 (0.65), 7.658 (0.64), 9.871 (1.14).

Example 2151-(4-[(2,6-dichlorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Synthesized analogously to Example 211 from Example 132 LC-MS (MethodA): R_(t)=1.08 min; MS (ESIpos): m/z=551 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.155 (1.67), 1.173 (3.63), 1.190(1.86), 1.237 (0.84), 1.255 (1.82), 1.273 (0.82), 1.442 (1.52), 1.458(1.52), 1.988 (6.89), 2.332 (0.41), 2.518 (2.30), 2.523 (1.54), 2.539(16.00), 4.000 (0.65), 4.006 (0.68), 4.017 (1.69), 4.024 (0.68), 4.035(1.58), 4.053 (0.49), 5.759 (0.80), 7.409 (0.60), 7.429 (0.55), 7.553(0.75), 7.577 (0.78), 7.585 (2.17), 7.606 (1.58), 7.653 (0.48), 7.668(0.47), 10.275 (1.05).

Example 2161-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid

Synthesized analogously to Example 211 from Example 187 LC-MS (MethodA): R_(t)=1.03 min, MS (ESIpos): m/z=535 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.149 (9.59), 1.154 (5.51), 1.172(8.74), 1.180 (9.39), 1.190 (4.47), 1.239 (7.38), 1.257 (15.42), 1.275(7.26), 1.389 (5.70), 1.406 (5.96), 1.437 (12.96), 1.454 (12.96), 1.641(1.04), 1.657 (1.68), 1.674 (1.10), 1.691 (0.45), 1.907 (1.75), 1.988(16.00), 2.085 (0.65), 2.234 (1.68), 2.253 (3.04), 2.271 (1.49), 2.323(2.79), 2.327 (3.69), 2.331 (2.79), 2.523 (12.44), 2.540 (2.59), 2.665(2.79), 2.669 (3.76), 2.673 (2.79), 3.982 (1.94), 3.999 (7.00), 4.017(9.26), 4.035 (5.38), 4.053 (1.30), 4.151 (0.45), 4.168 (1.43), 4.185(1.43), 4.936 (0.91), 4.952 (2.14), 4.968 (2.79), 4.984 (2.01), 5.000(0.78), 5.759 (1.04), 7.364 (1.23), 7.383 (2.91), 7.400 (1.81), 7.408(2.53), 7.431 (2.85), 7.445 (3.24), 7.456 (6.02), 7.462 (7.19), 7.476(1.62), 7.511 (2.40), 7.533 (5.31), 7.555 (3.37), 7.571 (3.17), 7.591(1.55), 10.434 (7.90).

Example 2171-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[1,1-difluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid(Racemic)

Synthesized analogously to Example 211 from Example 180 LC-MS (MethodA): R_(t)=1.03 min; MS (ESIpos): m/z=499 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.149 (14.12), 1.154 (4.12), 1.172(5.56), 1.180 (14.06), 1.190 (2.88), 1.238 (7.37), 1.256 (16.00), 1.274(7.31), 1.389 (8.75), 1.406 (9.25), 1.430 (10.06), 1.446 (10.00), 1.622(0.50), 1.640 (1.50), 1.656 (2.50), 1.672 (1.62), 1.690 (0.63), 1.907(1.88), 1.987 (9.63), 2.233 (2.50), 2.252 (4.63), 2.270 (2.19), 2.322(2.63), 2.326 (3.56), 2.331 (2.56), 2.522 (11.00), 2.539 (2.12), 2.664(2.75), 2.668 (3.69), 2.673 (2.63), 3.989 (1.88), 3.999 (2.00), 4.007(5.94), 4.017 (3.75), 4.025 (5.81), 4.035 (3.19), 4.042 (1.81), 4.053(0.94), 4.151 (0.69), 4.168 (2.25), 4.184 (2.19), 4.201 (0.69), 4.941(1.12), 4.951 (1.06), 5.758 (0.44), 6.183 (1.06), 6.190 (1.00), 6.320(2.06), 6.328 (2.06), 6.457 (0.94), 6.465 (1.00), 7.333 (1.19), 7.353(2.88), 7.371 (1.94), 7.377 (2.12), 7.382 (1.56), 7.403 (2.63), 7.417(2.75), 7.423 (2.00), 7.436 (6.12), 7.441 (5.06), 7.457 (1.75), 7.704(2.75), 7.730 (3.19), 7.902 (4.63), 7.923 (8.19), 8.133 (0.44), 9.668(8.81).

Example 2181-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 211 from Example 119 LC-MS (MethodA): R_(t)=0.99 min; MS (ESIpos): m/z=521 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.442 (2.28), 1.458 (2.31), 1.907(0.43), 2.084 (3.00), 2.518 (2.08), 2.523 (1.41), 2.539 (16.00), 3.334(0.76), 5.335 (0.45), 7.360 (0.55), 7.384 (0.42), 7.412 (0.51), 7.426(0.60), 7.436 (1.14), 7.443 (1.43), 7.590 (0.91), 7.614 (0.90), 7.638(0.80), 7.652 (0.79), 10.126 (1.81).

Example 2191-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 211 from Example 127 LC-MS (MethodA): R_(t)=0.99 min, MS (ESIpos): m/z=501 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.436 (6.98), 1.452 (7.09), 1.907(0.90), 2.084 (12.28), 2.278 (16.00), 2.518 (3.69), 2.523 (2.44), 3.340(1.00), 5.320 (0.43), 5.335 (1.06), 5.351 (1.40), 5.367 (1.03), 5.383(0.41), 7.105 (0.92), 7.120 (2.06), 7.125 (2.21), 7.137 (2.57), 7.147(1.42), 7.230 (1.08), 7.244 (1.17), 7.250 (1.60), 7.264 (1.25), 7.269(0.79), 7.283 (0.66), 7.602 (3.63), 7.621 (3.11), 7.626 (4.12), 7.636(2.93), 8.136 (0.47), 9.875 (4.42).

Example 2201-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

N-(2,6-difluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Example 96, 1.19 g, 2.43 mmol) was suspended in acetonitrile (10 mL)and water (10 mL). (Diacetoxyiodo)benzene (1.95 g, 6.07 mmol) was added,followed by TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl, 37.9 mg, 243μmol). The mixture was stirred for 16 h at room temperature. Sodiumhydroxide solution (1M) was added until the mixture was basic and theaqueous phase was washed with DCM. The aqueous phase was acidified withHCl (1N) and extracted with DCM twice. The combined organic phases weredried over sodium sulfate, filtered, and concentrated. Silica gelchromatography (DCM/MeOH) afforded the desired product (233 mg, 90%purity, 17% yield).

LC-MS (Method A): R_(t)=0.93 min; MS (ESIneg): m/z=503 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.437 (14.48), 1.453 (14.44), 1.908(2.02), 2.327 (0.74), 2.331 (0.56), 2.665 (0.57), 2.669 (0.76), 2.673(0.59), 3.166 (0.64), 3.230 (0.64), 3.247 (0.69), 3.280 (1.11), 3.311(2.86), 3.387 (1.34), 3.492 (2.12), 3.632 (0.40), 4.476 (0.86), 5.282(1.03), 5.297 (2.32), 5.313 (2.97), 5.329 (2.23), 5.344 (0.92), 5.759(16.00), 7.192 (4.65), 7.212 (9.56), 7.233 (5.92), 7.372 (1.07), 7.388(2.37), 7.408 (3.37), 7.425 (1.86), 7.429 (1.86), 7.445 (0.77), 7.577(6.72), 7.587 (6.01), 7.601 (10.94), 9.663 (0.52), 10.024 (11.69).

Example 2211-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 220 from Example 182

LC-MS (Method A): R_(t)=1.08 min; MS (ESIpos): m/z=549 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.877 (6.93), 0.896 (16.00), 0.914(7.41), 1.444 (9.58), 1.460 (9.54), 1.653 (0.52), 1.670 (2.09), 1.689(3.68), 1.707 (3.55), 1.726 (1.96), 1.745 (0.43), 2.074 (1.81), 2.084(0.80), 2.323 (0.78), 2.327 (1.10), 2.331 (0.78), 2.518 (4.56), 2.523(3.02), 2.665 (0.77), 2.669 (1.06), 2.673 (0.75), 3.344 (1.72), 3.925(3.06), 3.944 (4.44), 3.961 (2.86), 5.318 (0.60), 5.334 (1.46), 5.350(1.87), 5.366 (1.36), 5.382 (0.54), 5.759 (5.40), 7.342 (1.03), 7.361(2.30), 7.377 (1.40), 7.385 (1.75), 7.393 (1.14), 7.413 (2.18), 7.426(2.60), 7.437 (4.78), 7.443 (5.92), 7.458 (1.18), 7.592 (3.81), 7.616(3.72), 7.671 (3.36), 7.686 (3.29), 10.127 (7.62).

Example 2221-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-5-{[3,3-difluorobutan-2-yl]oxy}-2-fluorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid (Racemic)

Synthesized analogously to Example 220 from Example 185

LC-MS (Method A): R_(t)=1.02 min; MS (ESIpos): m/z=531 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.249 (4.49), 1.267 (9.83), 1.284(4.47), 1.303 (0.42), 1.322 (0.53), 1.346 (7.18), 1.361 (7.08), 1.653(4.09), 1.702 (7.88), 1.751 (3.65), 2.074 (0.59), 2.084 (16.00), 2.322(0.95), 2.326 (1.23), 2.331 (0.89), 2.522 (4.75), 2.664 (0.93), 2.669(1.21), 2.673 (0.89), 3.985 (1.19), 4.002 (3.58), 4.020 (3.50), 4.037(1.10), 4.877 (0.53), 4.901 (0.95), 4.917 (0.97), 7.341 (0.72), 7.345(0.78), 7.365 (1.80), 7.382 (1.14), 7.388 (1.42), 7.394 (1.04), 7.414(1.72), 7.427 (1.93), 7.434 (1.78), 7.441 (3.62), 7.447 (4.39), 7.462(0.97), 7.467 (0.70), 7.599 (3.18), 7.607 (2.90), 7.622 (5.09), 10.073(5.79).

Example 2231-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 220 from Example 181

LC-MS (Method A): R_(t)=1.02 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.939 (0.47), 0.984 (9.11), 0.995(16.00), 1.309 (0.54), 1.437 (9.98), 1.453 (9.92), 2.080 (4.11), 2.323(0.58), 2.665 (0.58), 3.096 (0.85), 3.110 (1.95), 3.123 (2.67), 3.135(1.88), 3.150 (0.88), 3.340 (1.91), 5.275 (0.67), 5.291 (1.53), 5.307(1.95), 5.322 (1.47), 5.337 (0.63), 5.755 (1.12), 7.336 (1.11), 7.355(2.49), 7.372 (1.42), 7.379 (1.76), 7.387 (1.26), 7.408 (2.21), 7.421(2.74), 7.432 (5.05), 7.438 (5.73), 7.452 (1.28), 7.573 (3.62), 7.597(3.64), 7.616 (3.52), 7.630 (3.43), 10.117 (7.08).

Example 2241-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 220 from Example 107

LC-MS (Method A): R_(t)=0.98 min, MS (ESIpos): m/z=519 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.103 (0.72), 1.120 (0.43), 1.137(0.80), 1.251 (7.48), 1.269 (15.37), 1.286 (7.61), 1.439 (12.44), 1.455(12.09), 1.907 (5.00), 2.084 (2.93), 2.327 (1.06), 2.331 (0.80), 2.669(1.15), 3.349 (1.72), 3.503 (0.63), 3.566 (16.00), 3.987 (2.81), 4.004(6.30), 4.021 (5.72), 4.039 (1.87), 4.486 (0.50), 5.286 (0.91), 5.301(1.96), 5.317 (2.57), 5.333 (1.98), 5.349 (0.89), 5.758 (4.20), 7.196(3.85), 7.217 (7.87), 7.237 (4.93), 7.377 (0.87), 7.393 (1.98), 7.414(2.89), 7.431 (1.63), 7.450 (0.69), 7.578 (0.72), 7.602 (0.59), 7.626(4.63), 7.650 (5.07), 7.659 (4.89), 7.673 (4.39), 7.705 (0.69), 7.720(0.61), 9.652 (1.43), 10.001 (0.54), 10.062 (8.74), 10.090 (1.15).

Example 2251-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 220 from Example 184

LC-MS (Method A): R_(t)=1.05 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.444 (14.87), 1.460 (15.35), 1.907(0.79), 2.322 (1.44), 2.327 (2.02), 2.332 (1.50), 2.522 (16.00), 2.539(6.80), 2.665 (1.47), 2.669 (1.95), 2.673 (1.44), 3.339 (6.19), 4.612(7.62), 4.625 (8.00), 5.066 (4.00), 5.069 (4.03), 5.109 (4.38), 5.112(4.44), 5.173 (4.62), 5.176 (4.48), 5.199 (4.99), 5.202 (4.85), 5.328(0.96), 5.344 (2.22), 5.360 (2.97), 5.376 (2.29), 5.391 (0.96), 5.758(1.74), 5.922 (1.13), 5.934 (2.56), 5.947 (2.12), 5.960 (2.70), 5.978(2.67), 5.990 (1.98), 6.004 (2.26), 6.017 (0.96), 6.971 (1.40), 7.099(1.81), 7.227 (1.44), 7.340 (1.61), 7.360 (3.66), 7.376 (2.26), 7.383(2.80), 7.392 (1.98), 7.411 (3.49), 7.425 (4.10), 7.436 (7.59), 7.442(9.33), 7.456 (2.19), 7.585 (5.78), 7.609 (5.74), 7.669 (5.09), 7.684(5.13), 10.122 (11.62).

Example 2261-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicAcid

Synthesized analogously to Example 220 from Example 183

LC-MS (Method A): R_(t)=1.12 min; MS (ESIpos): m/z=561 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.172 (0.43), 1.442 (8.65), 1.458(8.79), 1.666 (0.57), 1.687 (1.15), 1.712 (1.51), 1.732 (1.33), 1.754(1.61), 1.778 (1.26), 1.907 (0.90), 1.988 (0.75), 2.160 (0.93), 2.181(2.55), 2.188 (1.87), 2.203 (2.51), 2.223 (0.97), 2.336 (0.86), 2.518(16.00), 2.522 (9.47), 2.539 (3.52), 2.678 (0.75), 2.884 (0.54), 2.909(1.87), 2.935 (2.58), 2.961 (1.79), 2.986 (0.54), 5.237 (1.29), 5.259(1.90), 5.281 (1.29), 5.311 (0.61), 5.327 (1.33), 5.343 (1.72), 5.359(1.29), 5.374 (0.54), 5.758 (1.51), 6.960 (1.15), 7.087 (1.40), 7.215(1.18), 7.335 (0.86), 7.340 (0.97), 7.359 (2.15), 7.376 (1.29), 7.383(1.61), 7.390 (1.11), 7.411 (2.01), 7.424 (2.37), 7.435 (4.45), 7.442(5.56), 7.456 (1.18), 7.461 (0.75), 7.572 (3.48), 7.596 (3.41), 7.636(2.83), 7.651 (2.87), 8.598 (0.72), 10.061 (0.43), 10.114 (6.71).

Example 2271-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid (Example 220, 100 mg, 198 μmol) was dissolved in DCM (7 mL) and DMF(0.76 μl, 9.9 μmol). Oxalyl chloride (35 μl, 400 μmol) was addeddropwise and the mixture was stirred at room temperature for 20 min. Themixture was concentrated to yield the crude acid chloride.

The acid chloride was dissolved in DCM (2 mL) and added to a mixture ofammonia in dioxane (1.2 ml, 0.50 M, 590 μmol), trimethylamine (55 μl,400 μmol) and DCM (2 mL), cooled to 0° C.

The mixture was stirred at 0° C. for 1 h. The mixture was diluted withDCM and washed with water, dilute HCl, and saturated sodium bicarbonatesolution. The organic phase was dried over sodium sulfate, filtered andconcentrated. prepHPLC yields the desired compound (24.1 mg (95% purity,23% yield).

LC-MS (Method A): R_(t)=1.09 min, MS (ESIpos): m/z=504 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.443 (6.24), 1.459 (6.16), 2.084(9.13), 2.326 (0.84), 2.668 (0.85), 3.482 (16.00), 5.236 (0.43), 5.252(0.98), 5.267 (1.29), 5.283 (0.97), 5.299 (0.41), 5.758 (1.95), 7.197(1.85), 7.217 (3.79), 7.237 (2.33), 7.377 (0.42), 7.393 (0.95), 7.414(1.35), 7.430 (0.77), 7.626 (2.40), 7.651 (3.11), 7.670 (2.27), 8.000(2.10), 8.208 (2.26), 10.039 (3.60).

Example 2281-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

Synthesized analogously to Example 227 from Example 212 and aqueousammonia.

LC-MS (Method A): R_(t)=1.17 min, MS (ESIpos): m/z=534 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.154 (4.24), 1.172 (8.57), 1.190(4.42), 1.241 (4.69), 1.258 (9.64), 1.276 (4.86), 1.451 (7.96), 1.467(7.87), 1.885 (2.56), 1.988 (16.00), 2.323 (3.80), 2.327 (5.13), 2.331(3.98), 2.665 (3.89), 2.669 (5.22), 2.673 (3.98), 3.999 (2.03), 4.017(5.48), 4.035 (5.48), 4.053 (2.12), 5.316 (1.33), 5.333 (1.15), 5.759(7.43), 7.361 (1.59), 7.385 (1.15), 7.413 (1.24), 7.427 (1.59), 7.438(3.01), 7.444 (3.36), 7.593 (2.83), 7.617 (2.39), 7.650 (1.50), 7.688(2.03), 7.702 (1.94), 8.029 (1.86), 8.237 (2.03), 10.104 (3.27).

Example 229N-cyclopropyl-1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

Synthesized analogously to Example 227 from Example 224 andcyclopropanamine.

LC-MS (Method A): R_(t)=1.27 min; MS (ESIneg): m/z=556 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.638 (1.35), 0.646 (1.84), 0.656(0.76), 0.682 (0.73), 0.692 (1.42), 0.711 (1.46), 1.248 (1.81), 1.265(3.94), 1.283 (1.96), 1.436 (2.98), 1.451 (3.14), 2.084 (16.00), 2.327(0.42), 2.669 (0.42), 2.846 (0.58), 2.857 (0.64), 2.865 (0.42), 3.980(0.52), 3.997 (1.56), 4.015 (1.55), 4.032 (0.52), 5.275 (0.47), 5.290(0.63), 5.306 (0.49), 5.759 (15.65), 7.197 (0.95), 7.217 (2.02), 7.238(1.28), 7.395 (0.48), 7.415 (0.72), 7.435 (0.41), 7.621 (1.25), 7.645(1.21), 7.683 (1.11), 7.697 (1.14), 8.987 (0.87), 8.998 (0.90), 10.027(1.11).

Example 2301-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-N,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

Synthesized analogously to Example 227 from Example 220 and methanaminein THF (2M).

LC-MS (Method A): R_(t)=1.13 min; MS (ESIpos): m/z=518 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.439 (5.06), 1.455 (5.02), 2.331(1.46), 2.336 (0.69), 2.518 (8.30), 2.523 (5.47), 2.761 (7.98), 2.774(7.82), 3.485 (16.00), 5.253 (0.77), 5.269 (1.01), 5.285 (0.77), 7.193(1.26), 7.214 (2.55), 7.234 (1.54), 7.388 (0.57), 7.408 (0.77), 7.626(1.90), 7.650 (2.35), 7.671 (1.34), 8.801 (1.17), 8.813 (1.17), 10.043(2.59).

Example 2311-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylicacid (Example 224, 100 mg, 193 μmol) was dissolved in DCM (2 mL).1-Chloro-1-dimethylamino-2-methyl-1-propene (38 μl, 290 μmol) was addeddropwise and the mixture was stirred at room temperature for 30 min.Ammonia in methanol (7M) was added and the mixture was stirred at roomtemperature overnight. The mixture was diluted with water and wasextracted with DCM (2×). The combined organic phases were dried oversodium sulfate, filtered and concentrated. prepHPLC yielded the desiredcompound (45.0 mg, 90% purity, 41% yield) as well as Example 232 andExample 233.

LC-MS (Method A): R_(t)=1.15 min, MS (ESIpos): m/z=518 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.239 (4.13), 1.257 (8.41), 1.274(4.19), 1.300 (0.60), 1.444 (6.92), 1.460 (6.60), 2.084 (2.01), 2.326(1.02), 2.668 (1.06), 3.040 (0.76), 3.216 (0.78), 3.298 (0.60), 3.929(0.57), 3.995 (1.22), 4.012 (3.32), 4.030 (3.23), 4.047 (1.09), 5.256(0.46), 5.272 (1.04), 5.288 (1.38), 5.304 (1.08), 5.320 (0.55), 5.758(16.00), 7.196 (2.10), 7.217 (4.27), 7.237 (2.63), 7.376 (0.48), 7.393(1.11), 7.413 (1.52), 7.429 (0.92), 7.625 (2.51), 7.649 (2.56), 7.679(2.35), 7.693 (2.26), 8.026 (2.03), 8.237 (2.28), 10.032 (1.27).

Example 2321-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-N,N-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

Isolated during the synthesis Example 231

LC-MS (Method A): R_(t)=1.22 min; MS (ESIneg): m/z=544 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.242 (3.47), 1.260 (7.38), 1.277(3.52), 1.440 (5.20), 1.456 (5.20), 2.327 (0.61), 2.669 (0.62), 3.041(15.95), 3.217 (16.00), 3.756 (0.96), 3.773 (2.95), 3.791 (2.89), 3.809(0.93), 5.284 (0.83), 5.299 (1.08), 5.315 (0.80), 5.760 (2.07), 7.193(1.53), 7.214 (3.19), 7.234 (1.95), 7.389 (0.77), 7.410 (1.09), 7.426(0.63), 7.611 (2.00), 7.635 (2.04), 7.651 (1.88), 7.666 (1.82), 10.027(3.34).

Example 233 methyl1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylate

Isolated during the synthesis Example 231

LC-MS (Method A): R_(t)=1.27 min; MS (ESIneg): m/z=531 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.265 (3.38), 1.271 (2.25), 1.282(6.96), 1.300 (3.50), 1.320 (1.45), 1.338 (0.71), 1.437 (5.66), 1.453(5.56), 2.322 (1.05), 2.327 (1.40), 2.331 (0.98), 2.522 (6.20), 2.665(1.10), 2.669 (1.45), 2.673 (1.03), 3.040 (0.44), 3.217 (0.44), 3.809(0.56), 3.828 (0.54), 3.930 (16.00), 3.983 (1.13), 4.000 (2.89), 4.018(2.72), 4.035 (0.86), 4.927 (1.57), 5.304 (0.93), 5.320 (1.25), 5.336(0.98), 5.351 (0.44), 5.760 (4.61), 7.195 (1.81), 7.215 (3.72), 7.236(2.25), 7.376 (0.42), 7.391 (0.96), 7.412 (1.27), 7.429 (0.76), 7.594(0.42), 7.619 (0.71), 7.633 (2.23), 7.657 (3.75), 7.672 (1.81), 7.686(0.44), 9.651 (0.91), 10.072 (2.25).

Example 2345-fluoro-4-{3-[1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Mixture of Stereoisomers)

Step A

5-fluoro-4-{3-[(1R)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Example 73, 150 mg, 311 μmol) was dissolved in dichloromethane (10 mL).Dess-Martin-periodinane(1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 198 mg,466 μmol) was added and the mixture was stirred overnight at roomtemperature. The mixture was diluted with water and extracted with DCM(3×). The combined organic phases were washed with sat. sodiumbicarbonate solution and brine, dried over sodium sulfate, filtered andconcentrated to yield crude4-(3-acetyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(159 mg, 106% yield, LC-MS (Method A): R_(t)=1.30 min; MS (ESIpos):m/z=481 [M+H]⁺).

Step B

The crude ketone from above (159 mg, 331 μmol) was dissolved in methanol(2 mL) and THF (1.5 mL) and cooled to 0° C. Sodium borohydride (22.5 mg,596 μmol) was added and the mixture was stirred at 0° C. for anadditional 30 min. The reaction was quenched with saturated ammoniumchloride solution (10 mL) and extracted with DCM (3×). The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. PrepHPLC yielded the desired product (47.0 mg, 90% purity,26% yield).

LC-MS (Method A): R_(t)=1.17 min; MS (ESIpos): m/z=483 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.438 (2.09), 1.458 (3.81), 1.474(3.06), 2.263 (5.20), 2.518 (0.69), 2.523 (0.46), 3.334 (16.00), 3.343(7.64), 4.792 (0.49), 5.361 (0.42), 5.828 (0.59), 5.843 (0.58), 7.145(0.63), 7.148 (0.63), 7.163 (0.51), 7.167 (0.49), 7.223 (0.58), 7.251(0.68), 7.269 (0.48), 7.478 (0.72), 7.495 (0.61), 7.545 (0.86), 7.560(0.85), 7.641 (1.09), 7.666 (1.10), 9.729 (1.24).

Example 2354-{4-ethyl-5-oxo-3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Mixture of Stereoisomers)

Step A

4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(Example 124, 620 mg, 95% purity, 1.15 mmol) was dissolved indichloromethane (15 mL). Dess-Martin-periodinane(1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 730 mg,1.72 mmol) was added and the mixture was stirred for 2 h at roomtemperature. The mixture was diluted with water and extracted with DCM(3×). The combined organic phases were washed with sat. sodiumbicarbonate solution and brine, dried over sodium sulfate, filtered andconcentrated to yield crude4-(4-ethyl-3-formyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide(695 mg, 90% purity, 107% yield, LC-MS (Method B): R_(t)=1.14 min, MS(ESIneg): m/z=510 [M−H]⁻).

Step B

The crude aldehyde from above (200 mg, 391 μmol) was dissolved in THF (2mL) and cooled to 0° C. TBAF (tetra-n-butylammonium fluoride, 1M in THF,20 μl, 20 μmol) was added followed by trifluoromethyltrimethylsilane(100 μl, 700 μmol). The resulting red solution was stirred at roomtemperature overnight. Additional TBAF (1M in THF, 20 μl, 20 μmol) wasadded followed by trifluoromethyltrimethylsilane (60 μl, 420 μmol) andthe mixture was stirred at room temperature for 2 days. The mixture wasfiltered and purified using prepHPLC to yield the desired product (32.0mg, 98% purity, 13% yield).

LC-MS (Method A): R_(t)=1.20 min, MS (ESIpos): m/z=582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.914 (1.42), 0.932 (3.62), 0.951(1.73), 1.230 (0.30), 1.258 (2.36), 1.275 (5.39), 1.293 (2.72), 1.314(0.76), 1.332 (0.44), 1.446 (3.95), 1.462 (3.96), 1.543 (0.34), 1.563(0.42), 1.605 (0.21), 2.223 (10.84), 2.336 (0.17), 2.470 (0.35), 2.474(0.37), 2.480 (0.49), 2.518 (2.32), 2.522 (1.45), 3.137 (0.49), 3.158(0.43), 3.179 (0.47), 3.810 (0.21), 3.829 (0.53), 3.847 (1.21), 3.862(16.00), 3.875 (1.28), 3.892 (0.49), 3.910 (0.20), 5.361 (0.25), 5.376(0.59), 5.392 (0.77), 5.408 (0.57), 5.425 (0.23), 5.517 (0.29), 5.534(0.77), 5.553 (0.72), 5.570 (0.24), 6.934 (1.91), 6.947 (2.04), 7.583(2.26), 7.598 (1.68), 7.608 (2.56), 7.613 (1.78), 7.969 (2.59), 7.983(2.57), 9.680 (1.27).

Experimental Section—Reference Compounds Reference Compound 14-[3-(2,6-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxy-N-[3-(tri-fluoromethyl)phenyl]benzamide

Synthesis described in WO 2013/186692 A1, Example-70.

Experimental Section—Biological Assays

The following table 2 lists the abbreviations used herein, in particularin the Biological Assays Part of the Experimental Section:

TABLE 2 Abbreviations ATCC American Type Culture Collection DDK Name ofa polypeptide tag DCM dichloromethane DHODH Dihydroorotate DehydrogenaseDMSO dimethylsulfoxide h hour(s) IC₅₀ half maximal inhibitoryconcentration μM micromolar mM millimolar MTP Microtiter plate MYC nameof a polypeptide tag μl microliter nM nanomolar PBS Phosphate BufferedSaline RPMI Roswell Park Memorial Institute rt room temperature THP cellline name Triton X name of a detergent Tristris(hydroxymethyl)aminomethane

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

The in vitro activity of the compounds of the present invention can bedemonstrated in the following assays:

In Vitro Assay 1: DHODH Enzymatic Assay—1

The enzymatic assay couples DHODH activity with bleaching of the dye2,6-dichlorophenolindophenol (DCIP) (Knecht and Loffler, 1998; Miller etal., 1968). The assay was conducted in buffer containing 50 mM Tris,0.1% Triton X-100, 150 mM potassium chloride, 2 nM DHODH, 1 mMdihydroorotate, 0.1 mM decylubiquinone, 0.06 mM DCIP, and 2% DMSO at pH8.0 at 32 degree celsius. The reaction was initiated by addition ofsubstrates. Enzyme activity was monitored kinetically by the reductionin DCIP absorbance at 600 nm. Purified recombinant human DHODH enzymewas purchased from Novus (cat. no. NBP1-98916). Other chemicals werepurchased from Sigma-Aldrich. Absorbance measurements were obtainedusing a BMG clarion star plate-reading spectrophotometer.

In Vitro Assay 2: DHODH Enzymatic Assay—2

The enzymatic assay couples DHODH activity with bleaching of the dye2,6-Dichlorophenolindophenol (DCIP) (Knecht and Loffler, 1998; Miller etal., 1968). The assay was conducted in aqueous buffer containing 50 mMTris, 0.1% Triton X-100, 150 mM potassium chloride, 0.4 μg/mL DHODH, 1mM dihydroorotate, 0.1 mM decylubiquinone, 0.06 mM DCIP, and 0.17% DMSOat pH 8.0 at room temperature. Compounds were added via pin transfer orvia D300 digital dispenser, and the reaction was initiated by additionof substrates. Enzyme activity was monitored kinetically by thereduction in DCIP absorbance at 600 nm. Purified recombinant human DHODH(full-length, C-terminal MYC/DDK-tag) enzyme was purchased from Origene(cat. no. TP039034). Other chemicals, including leflunomide andteriflunomide, were purchased from Sigma-Aldrich. Absorbancemeasurements were obtained using a Molecular Devices Spectramax M5plate-reading spectrophotometer.

In Vitro Assay 3: H460 (Lung Cancer)

Alamar Blue:

4000 cells/well of NCI-H460 cells were seeded in 90% RPMI 1640(Invitrogen, #22400-089) and 10% fetal bovine serume (Invitrogen,#10099-141) and Penicillin/Streptomycin in 96 well plates. The next day,cells were incubated with different concentrations of test compounds for72 h. Cellular viability was analysed incubating cells with 12 μl ofAlamar Blue (Invitrogen) per well for 2 hours at 37° C. Finally theplate was analysed using exitation wavelength: 544 nm and emissionwavelength: 590 nm.

CellTiter-Glo®:

250 cells/well of NCI-H460 cells were seeded in 90% RPMI 1640(Invitrogen, #22400-089) and 10% fetal bovine serume (Invitrogen,#10099-141) and Penicillin/Streptomycin in 96 well plates. The next day,cells were incubated with different concentrations of test compounds for72 h. Cellular viability was analyzed using CellTiter-Glo® LuminescentCell Viability Assay (Promega, #G7572) according to manufacturer'sinstructions.

In vitro Assay 4: THP-1 Proliferation Assay—1 (AML)

2000 cells/well of THP-1 cells were seeded in RPMI 1640 with Glutamax(Gibco, #11875-093) and 10% fetal calf serum (Biochrom, #S0615) in384-well plates. The next day, cells were incubated with differentconcentrations of test compounds for 72 h. Cellular viability wasanalyzed using CellTiter-Glo® Luminescent Cell Viability Assay (Promega,#G7570) according to manufacturer's instructions.

TABLE 3 IC₅₀ values of examples and reference compound in in vitroassays 1-4 In vitro Assay 4: In vitro Assay 1: In vitro Assay 2: Invitro Assay 3: THP-1 DHODH DHODH H460 proliferation enzymatic assay 1enzymatic assay 2 (lung cancer) assay Example IC₅₀ [mol/l] IC₅₀ [mol/l]IC₅₀ [mol/l] (AML) No (mean values) (mean values) (mean values) IC₅₀[mol/l] 1 4.43E−08 9.00E−09 3.73E−08 2 4.30E−08 1.40E−08 9.43E−08 34.25E−07 1.49E−07 4 2.27E−06 1.10E−06 5 2.00E−08 1.90E−08 6 3.85E−067.55E−07 7 5.25E−08 1.70E−08 3.12E−08 8 7.25E−08 5.20E−08 5.01E−08 95.00E−06 2.10E−06 10 1.40E−07 2.10E−08 11 4.80E−08 8.00E−09 7.18E−09 121.00E−07 1.70E−08 3.70E−08 13 3.50E−08 1.10E−08 14 2.35E−06 7.38E−07 158.00E−07 6.65E−07 16 5.33E−09 1.30E−05 8.00E−10 17 6.00E−09 1.00E−092.35E−09 18 5.22E−08 3.00E−09 4.78E−09 19 1.53E−07 6.43E−08 1.96E−086.21E−08 20 3.27E−07 5.68E−08 4.13E−08 21 7.50E−07 8.57E−08 6.65E−08 225.00E−07 7.16E−08 4.29E−08 23 3.00E−08 1.70E−06 2.00E−09 24 1.50E−085.40E−09 6.80E−09 25 26 1.50E−07 1.60E−05 3.17E−08 27 2.13E−07 9.60E−0928 2.80E−08 5.46E−08 1.20E−08 29 7.50E−07 8.49E−07 5.81E−08 30 2.52E−073.20E−08 31 8.00E−08 1.90E−07 2.25E−08 32 9.00E−10 33 1.60E−08 2.50E−0934 1.00E−07 4.09E−07 2.71E−08 35 1.60E−07 4.18E−07 2.37E−08 36 1.10E−082.80E−09 1.60E−09 37 2.00E−08 2.24E−08 7.80E−09 38 2.90E−08 3.77E−085.40E−09 2.16E−08 39 1.90E−07 5.50E−09 2.46E−08 40 4.50E−07 2.19E−073.25E−08 41 9.00E−07 1.10E−06 9.03E−08 42 2.00E−06 3.98E−08 43 7.00E−082.89E−07 1.12E−08 44 1.53E−08 3.50E−09 45 1.52E−07 1.50E−09 46 7.00E−073.50E−06 4.08E−08 47 1.70E−08 1.22E−08 48 7.50E−09 3.45E−09 49 1.60E−0750 5.00E−08 1.61E−08 51 1.40E−08 52 4.00E−07 53 1.25E−08 6.00E−09 546.05E−09 55 1.00E−07 56 1.20E−07 57 4.40E−08 58 5.00E−07 59 9.00E−081.65E−07 60 1.50E−08 61 4.00E−07 62 1.50E−07 63 4.50E−07 64 2.00E−06 651.30E−08 3.55E−08 66 5.00E−09 1.23E−08 67 9.00E−08 68 1.30E−08 3.98E−0969 1.50E−08 70 1.60E−07 71 7.75E−09 72 2.65E−08 1.92E−08 73 4.30E−083.60E−08 74 2.50E−06 1.10E−06 1.00E−12 75 7.20E−06 1.20E−12 76 2.00E−051.00E−12 77 3.29E−08 78 9.00E−10 79 1.90E−09 80 1.50E−09 81 7.00E−10 821.00E−06 1.50E−09 83 8.67E−07 2.90E−09 84 1.00E−09 85 2.12E−08 2.30E−0986 87 6.00E−10 88 1.00E−06 1.51E−08 89 1.21E−08 90 1.30E−05 2.93E−07 915.90E−06 1.38E−08 92 3.00E−05 93 9.00E−07 94 1.43E−08 95 5.43E−088.33E−08 96 4.98E−08 1.06E−07 97 3.00E−06 98 1.13E−07 8.75E−08 996.00E−08 7.42E−08 100 8.50E−06 101 7.00E−07 102 9.00E−07 103 6.50E−081.73E−07 104 1.50E−07 105 1.50E−08 2.24E−08 106 1.31E−08 1.59E−08 1071.43E−08 2.96E−08 108 1.10E−06 109 1.60E−08 3.40E−08 110 2.40E−07 1113.50E−08 3.68E−08 112 6.00E−07 113 5.00E−07 114 2.50E−06 115 1.50E−07116 1.60E−07 117 4.00E−06 118 8.50E−06 119 9.75E−09 8.66E−09 1206.17E−09 2.40E−09 121 4.17E−09 4.25E−09 122 1.50E−08 1.05E−08 1238.00E−08 9.33E−08 124 1.90E−08 3.33E−08 125 2.50E−08 3.20E−08 1261.40E−07 1.13E−07 127 1.95E−08 2.45E−08 128 4.50E−09 1.12E−08 1295.50E−09 6.28E−09 130 2.00E−08 1.77E−08 131 4.33E−09 6.64E−09 1323.00E−09 4.02E−09 133 4.50E−09 3.18E−09 134 3.50E−09 5.95E−09 1353.20E−09 2.21E−09 136 5.00E−09 3.51E−09 137 4.50E−09 7.23E−10 1381.50E−08 1.74E−08 139 2.30E−08 1.60E−08 140 1.50E−08 5.83E−09 1417.50E−09 4.28E−09 142 7.00E−09 1.73E−09 143 4.50E−09 1.02E−09 1446.00E−08 3.98E−08 145 1.30E−08 1.51E−08 146 2.20E−08 147 5.00E−062.00E−05 1.00E−12 148 149 2.00E−05 1.00E−13 150 1.80E−05 1.30E−12 1511.60E−06 7.10E−06 1.00E−12 152 2.00E−05 1.90E−05 1.00E−12 153 3.00E−068.70E−06 1.00E−13 154 7.50E−06 1.10E−05 1.00E−12 155 2.00E−05 1.00E−12156 157 9.28E−08 158 7.46E−08 159 1.00E−05 9.40E−06 1.00E−12 1607.86E−08 161 7.00E−06 2.00E−05 1.00E−12 162 2.00E−05 1.00E−13 1631.00E−12 164 2.00E−05 1.00E−13 165 5.02E−07 166 1.50E−07 2.95E−075.04E−08 167 9.29E−08 7.70E−09 168 4.00E−07 4.15E−08 1.46E−08 1699.00E−08 8.05E−08 1.51E−08 170 5.50E−07 2.46E−07 1.56E−07 171 1.00E−12172 1.80E−08 1.80E−09 3.60E−09 2.89E−08 173 2.50E−08 1.04E−07 9.10E−092.43E−08 174 5.50E−08 8.90E−09 3.80E−08 175 4.50E−09 176 3.90E−9 1.63E−9177 2.50E−8 2.00E−8 178 6.00E−9 3.29E−9 179 2.10E−8 2.16E−8 180 4.20E−81.95E−8 181 1.70E−8 4.53E−8 182 2.80E−9 2.63E−9 183 7.00E−9 1.54E−8 1842.50E−9 7.89E−9 185 1.00E−8 2.86E−9 186 1.20E−7 1.80E−7 187 2.50E−7 1884.50E−8 5.21E−8 189 2.00E−8 1.19E−8 190 5.00E−9 5.18E−8 191 2.40E−8 1924.30E−9 3.64E−9 193 5.20E−9 194 5.20E−9 195 2.80E−8 6.34E−9 196 4.50E−8197 4.20E−7 198 1.70E−7 199 8.50E−7 200 7.00E−8 201 2.20E−7 202 4.50E−8203 1.60E−7 204 5.50E−8 205 7.00E−8 206 6.50E−8 207 2.90E−6 208 3.10E−8209 6.50E−7 210 9.00E−6 211 6.00E−9 212 1.50E−9 5.08E−7 213 9.00E−9 2148.50E−9 215 1.50E−9 216 3.00E−7 217 5.00E−8 218 6.50E−9 2.48E−6 2192.50E−8 4.52E−6 220 4.00E−8 5.28E−7 221 1.00E−9 5.33E−7 222 7.00E−98.81E−7 223 1.40E−8 1.20E−7 224 7.50E−9 2.18E−7 225 2.00E−9 9.83E−7 2261.30E−8 8.59E−8 227 6.30E−8 7.54E−8 228 3.00E−9 1.33E−9 229 2.20E−7 2307.50E−7 231 2.00E−8 1.93E−8 232 1.50E−6 233 !2.35E−8 1.49E−7 234 2.50E−8235 1.70E−7 8.87E−8 Ref. Cpd. 1 3.00E−05 In accordance with furtherembodiments, the present invention provides compounds of general formula(I), that inhibit DHODH as described in in vitro assay 1 with an IC₅₀ ≤50 nM. In accordance with further embodiments, the present inventionprovides compounds of general formula (I), that inhibit DHODH asdescribed in in vitro assay 1 with an IC₅₀ ≤ 15 nM. In accordance withfurther embodiments, the present invention provides compounds of generalformula (I), that inhibit DHODH as described in in vitro assay 1 with anIC₅₀ ≤ 10 nM. In accordance with further embodiments, the presentinvention provides compounds of general formula (I), that have shownactivity in in vitro Assay 3. In accordance with further embodiments,the present invention provides compounds of general formula (I), thathave shown activity in any lung caner assay (in vitro or cell basedassay).In Vitro Assay 5: THP-1 Proliferation Assay—2

Tumor and normal cells were cultivated in their respective media (ATCCrecommended media). On day 1 of the assay, adherent cells were detachedfrom the culture vessels by trypsinization. Suspension cells werecentrifuged at 300×g and resuspended in fresh media. Cells were seededat densities of 300-1000 cells/30 μL/well in the inner wells of white384-well plates (Perkin Elmer). The outer wells of each plate werefilled with 60 μL PBS/well to reduce evaporation. One plate was used fortreatment of cells, the second plate was the start plate. All plateswere incubated at 37° C., 5% CO₂ for 24 hrs. On day 2, 30 μL/well ofCellTiter Glow (CTG, Promega) was added to the start plate, the platewas shaken at rt for 10 min on a laboratory plate shaker and then theplate was read in a Infinite M200 Pro MTP Reader (Tecan, Luminescence,0.1 s). Compounds from a 10 mM stock (in DMSO) were added in triplicatesto the treatment plate in tenfold dilutions (from 1E⁻⁶M to 1E⁻¹²M) witha HP D300 Digital Dispenser (the dispenser adds substances to wells innanoliter volumes, therefore any volume added with this device does notcount toward the final volume in the well). For rescue/specificityexperiments with uridine, 100 μM uridine/well (diluted from a 10 mMstock solution in DMSO; Sigma-Aldrich) were added with the HP D300Digital Dispenser. Treatment plates are incubated for a further 72 hrsat 37° C., 5% carbon dioxide, On day 5 of the assay, 30 μL/well ofCellTiter Glow (CTG, Promega) was added to the treatment plate, theplate was shaken at rt for 10 min on a laboratory plate shaker and thenthe plate was read in a Infinite M200 Pro MTP Reader (Tecan,Luminescence, 0.1 s).

In Vitro Assay 6: SUDHL-10 Proliferation Assay (Lymphom)

2000 cells/well of SUDHL-10 cells were seeded in RPMI 1640 with Glutamax(Gibco, #11875-093) and 10% fetal calf serum (Biochrom, #S0615) in384-well plates. The next day, cells were incubated with differentconcentrations of test compounds for 72 h. Cellular viability wasanalyzed using CellTiter-Glo® Luminescent Cell Viability Assay (Promega,#G7570) according to manufacturer's instructions.

In Vitro Assay 7: xCelligence Proliferation Assay (HCT116 (ColorectalCarcinoma, A498 (Kidney Carcinoma), Panc1 (Pancreas Carcinoma) CellLines)

Impedance measurement is a dimensionless parameter termed Cell Index(CI) which is derived as a relative change in measured electricalimpedance caused by an increase of cell number on the bottom of the cellculture well.

To determine CI, 2000 cells/well were seeded into 96-well E-plates.Cells were placed in the Real-Time Cell Analyzer (RTCA) station (ACEABiosciences) and incubated for 24 h. Subsequently, compounds were addedat concentrations as indicated and cells were replaced in the Real-TimeCell Analyzer (RTCA) station and analyzed until cells reach confluency.Impedance was measured every 60 min. Cell index was determined by thexCelligence software and presented as CI over time.

In Vitro Assay 8: U-87 MG Proliferation Assay (Glioblastoma)

U-87 MG cells were plated in MEM Earle's medium+10% FCS with 4000cells/well in a 96-well microtiter plate (d−1). Compound was added atd0. Cell number was determined by Alamar Blue staining (2 h) at d0 andd3. Fluorescence was determined in Victor3 (Excitation 530 nm; emission590 nm). C0 was defined as the signal measured at d4 for cells withouttreatment (0.1% DMSO). CI was defined as the signal measured at d0.

In Vitro Assay 9: Colo 205 Proliferation Assay (Colorectal Carcinoma)

COLO 205 cells were plated in RPMI1640 medium with stable glutamine+10%FCS+10 mM Hepes+1 mM Natriumpyruvat+1× Non Essential Amino Acids with4000 cells/well in a 96-well microtiter plate (d−1). Compound was addedat d0. Cell number was determined by Alamar Blue staining (2 h) at d0and d3. Fluorescence was determined in Victor3 (Excitation 530 nm;emission 590 nm). C0 was defined as the signal measured at d4 for cellswithout treatment (0.1% DMSO). CI was defined as the signal measured atd0.

in vitro assay 9: Colo 205 Example IC₅₀ [mol/l] No. (mean values) 13.0E−6In Vitro Assay 10: MKN-45 Proliferation Assay (Gastric Cancer)

MKN-45 cells were plated in RPMI1640 medium with stable glutamine+20%FCS with 4000 cells/well in a 96-well microtiter plate (d−1). Compoundwas added at d0. Cell number was determined by Alamar Blue staining (2h) at d0 and d3. Fluorescence was determined in Victor3 (Excitation 530nm; emission 590 nm). C0 was defined as the signal measured at d4 forcells without treatment (0.1% DMSO). CI was defined as the signalmeasured at d0.

TABLE 4 IC₅₀ values of examples in in vitro assay 10 in vitro assay 10:MKN-45 Example IC₅₀ [mol/l] No. (mean values) 1 2.6E−6In Vitro Assay 11: MIA PaCa2 Proliferation Assay (Pancreatic Carcinoma)

MIA PaCa 2 cells were plated in DMEM/HAMS F12 medium+10% FCS+2.5% HorseSerum with 4000 cells/well in a 96-well microtiter plate (d−1). Compoundwas added at d0. Cell number was determined by Alamar Blue staining (2h) at d0 and d3. Fluorescence was determined in Victor3 (Excitation 530nm; emission 590 nm). C0 was defined as the signal measured at d4 forcells without treatment (0.1% DMSO). CI was defined as the signalmeasured at d0.

In Vitro Assay 12: DU 145 Proliferation Assay (Prostate Cancer)

DU 145 cells were plated in DMEM/HAMS F12 medium+10% FCS with 4000cells/well in a 96-well microtiter plate (d−1). Compound was added atd0. Cell number was determined by Alamar Blue staining (2 h) at d0 andd3. Fluorescence was determined in Victor3 (Excitation 530 nm; emission590 nm). C0 was defined as the signal measured at d4 for cells withouttreatment (0.1% DMSO). CI was defined as the signal measured at d0.

TABLE 5 IC₅₀ values of examples in in vitro assay 12 in vitro assay 12:DU 145 Example IC₅₀ [mol/l] No. (mean values) 1 2.9E−7Assay 13: MOLM 13 Differentiation Assay (AML)

20000 cells per well of MOLM 13 cells were seeded in RPMI 1640 withGlutamax (Gibco, #11875-093) and 10% fetal calf serum (Biochrom, #S0615)and incubated with different concentrations of test compounds for 96 h.After treatment for 10 min with Human TruStain FcX, (Biolegend, #422302)or BD Human Fc Block (#564220) at RT, cells were incubated with 2 μg/mlAPC anti-mouse/human CD11b Antibody (Biolegend, Cat #101212) for 30 minat 4° C. Cells were analyzed by Fluorescence-activating cell sorting(FACS) (BD FACS Canto, BD Biosciences).

Assay 14: Cancer Cell Proliferation Panel

The CellTiter-Blue® Cell Viability Assay (#G8081, Promega) was usedaccording to manufacturer's instructions. Briefly, cells were harvestedfrom exponential phase cultures, counted and plated in 96-wellflat-bottom microtiter plates at a cell density of 4,000-60,000cells/well depending on the cell line's growth rate. After a 24 hrecovery period to allow the cells to resume exponential growth, 10 μlof culture medium (four control wells/plate) or of culture medium withtest compound were added. The compound was applied at 10 concentrationsin duplicate in half-log increments up to 30 μM and treatment continuedfor three days. After three days treatment of cells, 20 μl/wellCellTiter-Blue® reagent was added. Following an incubation period of upto four hours, fluorescence (FU) was measured by using the EnspireMultimode Plate Reader (excitation λ=531 nm, emission λ=615 nm).

For calculations, the mean values of duplicate/quadruplicate (untreatedcontrol) data were used.

TABLE 6 IC₅₀ values of Example 1 in assay 14 (Cancer Cell ProliferationPanel) Cell line Origin* abs IC₅₀ [μM] SF-539 gliosarcoma 0.221 HCT-116colorectal carcinoma 0.028 HT-29 colorectal carcinoma 0.041 SNU-899 head& neck cancer 0.235 CAL-27 head & neck cancer 0.087 Jurkat Leukemia0.014 MOLT-3 leukemia 0.029 MOLT-4 leukemia 0.019 HL-60 leukemia 0.026MOLM-13 leukemia 0.014 MV4-11 leukemia 0.033 EM-2 leukemia 0.037JURL-MK1 leukemia 0.047 SNU-398 hepatocellular carcinoma 0.1 SNU-449hepatocellular carcinoma 0.08 NCI-H460 lung cancer 0.147 NCI-H69 lungcancer 0.175 OCI-LY7 lymphoma 0.073 SUDHL-1 lymphoma 0.008 HUT-78lymphoma 0.029 MINO lymphoma 0.01 RAJI lymphoma 0.01 MDA-MB-453 breastcancer 0.112 SK-BR-3 breast cancer 0.289 MM.1S multiple myeloma 0.094OPM-2 multiple myeloma 0.032 IMR-32 neuroblastoma 0.005 SH-SY5Yneuroblastoma 0.032 A2780 ovarian cancer 0.033 PANC-1 pancreatic cancer0.041 PA-TU-8902 pancreatic cancer 0.281 PC-3M prostate cancer 0.306ACHN renal cell carcinoma 0.024 Caki-1 renal cell carcinoma 0.186HT-1080 sarcoma 0.025 SK-LMS-1 sarcoma 0.259Cell Proliferation Panel 2 Assay

Cells were grown in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mMNa pyruvate or a special medium. Cells were seeded into 384-well platesand incubated in a humidified atmosphere of 5% CO₂ at 37° C. Compoundswere added the day following cell seeding. At the same time, a time zerountreated cell plate was generated. After a 3-day incubation period,cells were fixed and stained to allow fluorescence imaging of nuclei.

Compounds were serially diluted in half-log steps from the highest testconcentration 10 μM, and assayed over 10 concentrations with a maximumassay concentration of 0.1% DMSO. Automated fluorescence microscopy wascarried out using a Molecular Devices ImageXpress Micro XL high-contentimager, and images were collected with a 4× objective. 16-bit TIFFimages were acquired and analyzed with MetaXpress 5.1.0.41 software.

Data Analysis

Cell proliferation was measured by the fluorescence intensity of anincorporated nuclear dye. The output is referred to as the relative cellcount, where the measured nuclear intensity is transformed to percent ofcontrol (POC) using the following formula:

$P\; O\; C{= {\frac{I_{x}}{I_{0}} \times 100}}$

Where I_(x) is the nuclear intensity at concentration x, and I₀ is theaverage nuclear intensity of the untreated vehicle wells.

Cellular response parameters were calculated using nonlinear regressionto a sigmoidal single-site dose response model:

$y = {A + \frac{B - A}{1 + \left( \frac{C}{x} \right)^{D}}}$

Where y is a response measured at concentration x, A and B are the lowerand upper limits of the response, C is the concentration at the responsemidpoint (EC₅₀), and D is the Hill Slope (Fallahi-Sichani, M., S.Honardejad, L. M. Heiser, J. W. Gray, and P. K. Sorger (2013). Metricsother than potency reveal systematic variation in responses to cancerdrugs. Nat. Chem. Biol. 9: 708-714.).

Time zero non-treated plates were used to determine the number ofdoublings during the assay period, using the formula:

${Doublings} = {\log_{2}\left( \frac{N}{N_{T0}} \right)}$

Where N is the cell number in untreated wells at the assay end point andN_(T0) is the cell number at the time of compound addition.

Cell count IC₅₀ is the test compound concentration at 50% of maximalpossible response. EC₅₀ is the test compound concentration at the curveinflection point or half the effective response (parameter C of thefitted curve solution).

Curve-fitting, calculations, and report generation was performed using acustom data reduction engine and MathIQ based software (AIM).

Cell Count EC50 Cell Count IC50 Compound Cell Line Origin (microM)(microM) Example 106 Colo 320DM Colorectal 3.40E−03 2.08E−02 carcinomaExample 106 786-O Renal cell 3.67E−03 1.71E−02 carcinoma Example 106A498 Renal cell >1.00E+01 >1.00E+01 carcinoma Example 106 ACHN Renalcell 1.34E−02 8.69E−02 carcinoma Example 106 ARH-77 Leukemia 3.21E−035.07E−03 Example 106 BC-1 Lymphoma 5.41E−03 9.14E−03 Example 106 BV-173Leukemia 1.13E−02 >1.00E+01 Example 106 Colo 205 Colorectal 2.83E−033.99E−03 carcinoma Example 106 CA46 Lymphoma 2.16E−02 1.45E−01 Example106 CCRFCEM Leukemia 3.39E−03 5.52E−03 Example 106 CEM-C1 Leukemia3.48E−03 4.95E−03 Example 106 CFPAC-1 Pancreatic 1.74E−02 6.43E−02cancer Example 106 CML-T1 Leukemia 1.24E−03 1.69E−03 Example 106 CaOV3Ovarian 3.21E−01 >1.00E+01 carcinoma Example 106 DMS114 Lung cancer3.40E−02 >1.00E+01 Example 106 Daudi Lymphoma 3.64E−03 5.90E−03 Example106 DLD-1 Colorectal 3.27E−03 1.97E−02 carcinoma Example 106 EM-2Leukemia 2.85E−03 5.46E−03 Example 106 G-401 Renal cell 5.53E−034.18E−02 carcinoma Example 106 HCT-15 Colorectal 1.80E−03 4.59E−03carcinoma Example 106 HCT-8 Colorectal 2.26E−03 4.23E−03 carcinomaExample 106 HCT-116 Colorectal 4.07E−03 7.95E−03 carcinoma Example 106HT-29 Colorectal 1.25E−02 7.54E−02 carcinoma Example 106 JeKo-1 Lymphoma6.22E−03 1.07E−02 Example 106 Jurkat Leukemia 2.47E−03 3.46E−03 Example106 K562 Leukemia 3.76E−03 4.74E−03 Example 106 MOLT-3 Leukemia 4.32E−035.59E−03 Example 106 MOLT-16 Leukemia 2.97E−03 3.84E−03 Example 106MEG01 Leukemia 2.53E−03 3.36E−02 Example 106 MHH-PREB-1 Lymphoma2.31E−03 2.54E−03 Example 106 Mia PaCa-2 Pancreatic 7.49E−03 >1.00E+01cancer Example 106 MV-4-11 Leukemia 2.74E−03 4.14E−03 Example 106NAMALWA Lymphoma 1.78E−03 4.13E−03 Example 106 NALM-6 Leukemia 3.25E−034.29E−03 Example 106 PA-1 Ovarian 7.49E−03 1.07E−02 carcinoma Example106 PANC-1 Pancreatic 2.29E−02 >1.00E+01 cancer Example 106 PSN-1Pancreatic 2.17E−03 1.24E−02 cancer Example 106 Raji Lymphoma 3.81E−036.04E−03 Example 106 Ramos (RA 1) Lymphoma 2.52E−03 3.11E−03 Example 106RPMI 8226 Multiple 1.02E−02 1.82E−02 Myeloma Example 106 SU-DHL-10Lymphoma 1.99E−04 >1.00E+01 Example 106 SHP-77 Lung cancer 7.46E−031.28E−01 Example 106 SU.86.86 Pancreatic 2.64E−02 >1.00E+01 cancerExample 106 U266B1 Multiple 3.45E−02 >1.00E+01 Myeloma Example 121 Colo320DM Colorectal 1.23E−03 5.10E−03 carcinoma Example 121 786-O Renalcell 8.59E−04 2.36E−03 carcinoma Example 121 A498 Renalcell >1.00E+01 >1.00E+01 carcinoma Example 121 ACHN Renal cell 3.12E−031.83E−02 carcinoma Example 121 ARH-77 Leukemia 9.20E−04 1.39E−03 Example121 BC-1 Lymphoma 1.02E−03 1.59E−03 Example 121 BV-173 Leukemia 9.06E−047.79E−02 Example 121 Colo 205 Colorectal 8.36E−04 1.22E−03 carcinomaExample 121 CA46 Lymphoma 3.11E−03 1.35E−02 Example 121 CCRFCEM Leukemia9.93E−04 1.56E−03 Example 121 CEM-C1 Leukemia 9.10E−04 1.28E−03 Example121 CFPAC-1 Pancreatic 4.55E−03 1.64E−02 cancer Example 121 CML-T1Leukemia 3.52E−04 4.95E−04 Example 121 CaOV3 Ovarian 1.29E−02 >1.00E+01carcinoma Example 121 DMS114 Lung cancer 7.62E−03 >1.00E+01 Example 121Daudi Lymphoma 6.13E−04 1.02E−03 Example 121 DLD-1 Colorectal 1.06E−034.01E−03 carcinoma Example 121 EM-2 Leukemia 1.06E−03 1.97E−03 Example121 G-401 Kidney cancer 2.19E−03 >1.00E+01 Example 121 HCT-15 Colorectal9.21E−04 2.83E−03 carcinoma Example 121 HCT-8 Colorectal 1.27E−032.34E−03 carcinoma Example 121 HCT-116 Colorectal 8.64E−04 1.67E−03carcinoma Example 121 HT-29 Colorectal 2.72E−03 1.10E−02 carcinomaExample 121 JeKo-1 Lymphoma 1.79E−03 3.01E−03 Example 121 JurkatLeukemia 6.38E−04 9.25E−04 Example 121 K562 Leukemia 1.03E−03 1.31E−03Example 121 MOLT-3 Leukemia 1.14E−03 1.49E−03 Example 121 MOLT-16Leukemia 8.42E−04 1.08E−03 Example 121 MEG01 Leukemia 6.60E−04 3.05E−03Example 121 MHH-PREB-1 Lymphoma 7.42E−04 8.30E−04 Example 121 Mia PaCa-2Pancreatic 2.23E−03 >1.00E+01 cancer Example 121 MV-4-11 Leukemia8.14E−04 1.20E−03 Example 121 NAMALWA Lymphoma 2.53E−04 1.56E−03 Example121 NALM-6 Leukemia 9.23E−04 1.27E−03 Example 121 PA-1 Ovarian 2.07E−032.88E−03 carcinoma Example 121 PANC-1 Pancreatic 3.50E−03 >1.00E+01cancer Example 121 PSN-1 Pancreatic 8.57E−04 6.46E−03 cancer Example 121Raji Lymphoma 8.56E−04 1.35E−03 Example 121 Ramos (RA 1) Lymphoma7.18E−04 8.78E−04 Example 121 RPMI 8226 Multiple 2.32E−03 4.21E−03Myeloma Example 121 SU-DHL-10 Lymphoma 1.26E−03 4.09E−03 Example 121SHP-77 Lung cancer 1.53E−03 1.63E−02 Example 121 SU.86.86 Pancreatic5.08E−03 >1.00E+01 cancer Example 121 U266B1 Multiple 4.88E−03 >1.00E+01Myeloma

What is claimed is:
 1. A method of treatment and/or prophylaxis of a hyperproliferative disease or an inflammatory disorder in a subject comprising administering to the subject a compound of formula (I):

in which R¹ represents a group selected from a C₅-C₈-alkyl group, a C₂-C₈-haloalkyl group, a C₄-C₈-cycloalkyl group, which is optionally partially unsaturated and which is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R⁷)(R⁸), and wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a cyano group, a hydroxy group, a phenyl group or a C₃-C₈-heterocycloalkyl group, a C₃-C₆-alkyl group which is substituted with a monocyclic—or bicyclic heteroaryl group, a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group, a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4-7-membered heterocycloalkyl group, a 5- to 7-membered heterocycloalkenyl group, wherein said 4-7-membered heterocycloalkyl group and said 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom, and which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O), wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, a phenyl group, which is optionally substituted, one, two, three, four or five times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), hydroxy, cyano, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₅-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl))-N(R⁷)(R⁸), —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —O—C(═O)—(C₁-C₆-alkyl), —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —N(O)₂, —P(═O)(C₁-C₃-alkyl)₂ and SF₅, or wherein two vicinal substituents may form together a 5- or 6-membered, optionally heterocyclic, aromatic or non-aromatic ring, having optionally 1-3 heteroatoms independently selected from —N═, —NH—, —N(R)—, —O—, —S—, and optionally containing a C(═O) group, and wherein the so formed ring is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₅-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —N(O)₂, and —N(R⁷)(R⁸) and a bicyclic aryl group, a partially saturated mono- or bicyclic aryl- or heteroaryl group, a monocyclic—or bicyclic heteroaryl group, which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₅-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, —O(C₂-C₆-alkenyl), C₃-C₅-cycloalkoxy, aryl, —O-aryl, cyano, C(═O)OR⁶, hydroxy, —SH, —(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸), R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from, a C₁-C₆-alkyl group, which is optionally substituted with a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₄-C₈-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group, a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl) group, wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is connected to the alkyl group via a carbon atom of the heterocycloalkyl group and which is optionally substituted with a C₁-C₃-alkyl group, and a phenyl group, which is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₅-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), —S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸) R⁴ represents a group selected from, a C₁-C₆-alkyl group, which is optionally substituted with a group selected from C₃-C₈-cycloalkyl and phenyl, wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₅-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₅-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸) a C₂-C₆-alkenyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl group, a C₂-C₆-hydroxyalkyl group, a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group, R⁵ represents a halogen atom or a group selected from a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₆-hydroxyalkyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group, a —(C₁-C₆-alkyl)-O—(C₁-C₆-alkyl) group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, and a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group, and a phenyl group which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, —(C₁-C₆-alkyl)-aryl, -aryl-(C₁-C₆-alkyl), C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, —O(C₂-C₆-alkenyl), C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR⁶, hydroxy, —SH, —S—(C₁-C₆-alkyl), —S—(C₂-C₆-alkenyl), S(═O)₂(C₁-C₆-alkyl), —S(═O)₂—(C₂-C₆-alkenyl), —N(O)₂, and —N(R⁷)(R⁸) R⁶ represents a hydrogen atom or a group selected from a C₁-C₆-alkyl group and a benzyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a group selected from a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a C₃-C₆-cycloalkyl group, and a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group, or R⁷ and R⁸ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 7-membered heterocycloalkyl group, which is optionally substituted with a group selected from C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl), R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen atom or a C₁-C₃-alkyl group, or R⁹ and R¹⁰ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 7-membered heterocycloalkyl group, R¹¹ represents a hydrogen atom or a group selected from a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 2. The method according to claim 1 in which R¹ represents a group selected from a C₅-C₈-alkyl group, a C₂-C₈-haloalkyl group, a C₄-C₈-cycloalkyl group, wherein said cycloalkyl groups are optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R⁷)(R⁸), wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, a C₁-C₆-alkyl group which is substituted with a C₃-C₈-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a cyano group, a hydroxy group or a phenyl group, a C₃-C₆-alkyl group which is substituted with a monocyclic—or bicyclic heteroaryl group, a (C₂-C₆-hydroxyalkyl)-O—(C₂-C₆-alky)- group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a —(C₃-C₈-cycloalkyl)-N(R⁷)(R⁸) group, a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 7-membered heterocycloalkyl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O), wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, and wherein said- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the said heterocycloalkyl- or heterocycloalkenyl group, a 5- to 7-membered heterocycloalkenyl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₆-alkyl), —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₆-alkyl) and oxo (═O), wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, and wherein said 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of the said heterocycloalkyl- or heterocycloalkenyl group, a phenyl group, wherein said phenyl group is optionally substituted, one, two, three, four or five times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₃-C₅-cycloalkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₅-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₆-alkyl)-N(R⁷)(R⁸), —(C₁-C₆-alkyl)-C(═O)OR⁶, —(C₁-C₆-alkyl)-C(═O)N(R⁷)(R⁸), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅, or in which two substituents of said phenyl groups, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and —NH—C(═O)—NH—, an indanyl group, a tetralinyl group wherein said indanyl or tetralinyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸), and a monocyclic—or bicyclic heteroaryl group, which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸), R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from a C₁-C₆-alkyl group, which is optionally substituted with a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₄-C₅-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group, a —(C₁-C₆-alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl) group and wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted with a C₁-C₃-alkyl group, and wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is connected to the alkyl group via a carbon atom of the heterocycloalkyl group, a phenyl group, wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, R⁴ represents a group selected from a C₂-C₆-alkylenyl group, a C₃-C₈-cycloalkyl group, a C₂-C₆-haloalkyl group, a C₂-C₆-hydroxyalkyl group and a-(C₂-C₆-alkyl)-N(R⁷)(R⁸) group, and a C₁-C₆-alkyl group, which is optionally substituted with a group selected from C₃-C₈-cycloalkyl and phenyl, wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₄-haloalkyl, C₁-C₃-alkoxy and hydroxy, R⁵ represents a halogen atom or a group selected from a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group, a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group, R⁶ represents a hydrogen atom or a group selected from a C₁-C₆-alkyl group and a benzyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a group selected from a C₁-C₆-alkyl group, a C₂-C₆-hydroxyalkyl group, a —(C₂-C₆-alkyl)-N(R⁹)(R¹⁰) group, and C₃-C₆-cycloalkyl group or R⁷ and R⁸ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted with a group selected from C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl), R⁹ and R¹⁰ represent, independently for each occurrence, a hydrogen atom or a C₁-C₃-alkyl group, or R⁹ and R¹⁰ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 7-membered heterocycloalkyl group, R¹¹ represents a hydrogen atom or a group selected from a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 3. The method according to claim 1, wherein R¹ represents a group selected from a C₅-C₈-alkyl group, a C₂-C₈-haloalkyl group, a C₄-C₈-cycloalkyl group, which is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R⁷)(R⁸), wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy, a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a cyano group, a hydroxy group or a phenyl group, a C₃-C₆-alkyl group which is substituted with a monocyclic or bicyclic heteroaryl group, a (C₂-C₃-hydroxyalkyl)-O—(C₂-C₆-alky)- group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a —(C₃-C₆-cycloalkyl)-N(R⁷)(R⁸) group, a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered heterocycloalkyl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl), —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O), wherein said 5- to 6-membered heteroaryl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy, wherein said 4- to 6-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom or nitrogen atom of the said heterocycloalkyl- or heterocycloalkenyl group, a 5- to 6-membered heterocycloalkenyl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C₁-C₄-alkyl), —C(═O)(C₁-C₃-alkyl), —C(═O)(C₃-C₆-cycloalkyl), —S(═O)₂(C₁-C₃-alkyl) and oxo (═O), wherein said 5- to 6-membered heteroaryl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy, wherein said 5- to 6-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom or nitrogen atom of the said heterocycloalkyl- or heterocycloalkenyl group, a phenyl group, which is optionally substituted, one, two, three, four or five times, each substituent independently selected from a halogen atom or a group selected from C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, hydroxy, cyano, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —(C₁-C₃-alkyl)-C(═O)OR⁶, —(C₁-C₃-alkyl)-C(═O)N(R⁷)(R⁸), —S(═O)₂N(R⁷)(R⁸), —S(═O)₂(C₁-C₃-alkyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl), —P(═O)(C₁-C₃-alkyl)₂ and SF₅, or in which two substituents of said phenyl groups, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from —CH₂—N(R⁷)—CH₂—, —CH₂—O—CH₂—, —O—CH₂—C(═O)—NH— and —NH—C(═O)—NH—, an indanyl group, which is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸), a tetralinyl group and which is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸), a monocyclic—or bicyclic heteroaryl group, which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkoxy, cyano, hydroxy and —N(R⁷)(R⁸), R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₁-C₆-hydroxyalkyl group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₄-C₆-cycloalkenyl group, a (C₁-C₆-alkyl)-N(R⁷)R⁸ group, a —(C₁-C₆-alkyl)-(4- to 6-membered nitrogen containing heterocycloalkyl) group and a phenyl group, wherein said C₁-C₆-alkyl group is optionally substituted with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group, and wherein said 4- to 6-membered nitrogen containing heterocycloalkyl group is optionally substituted with a C₁-C₃-alkyl group, and wherein said 4- to 6-membered nitrogen containing heterocycloalkyl group is connected to the alkyl group via a carbon atom of the heterocycloalkyl group, and wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy, R⁴ represents a group selected from a C₂-C₆-alkylenyl group, a C₃-C₆-cycloalkyl group, a C₂-C₆-haloalkyl group, a C₂-C₆-hydroxyalkyl group, a —(C₂-C₆-alkyl)-N(R⁷)(R⁸) group, and a C₁-C₆-alkyl group, which is optionally substituted with a group selected from C₃-C₆-cycloalkyl and phenyl, wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and hydroxy, R⁵ represents a halogen atom or a group selected from a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group, a C₂-C₆-alkenyl group, a C₂-C₆-alkynyl group, a C₁-C₆-alkoxy group, a C₁-C₆-alkylsulfanyl group, a —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group, a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group R⁶ represents a hydrogen atom or a group selected from a C₁-C₄-alkyl group and a benzyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a group selected from a C₁-C₃-alkyl group, a C₂-C₃-hydroxyalkyl group, a —(C₂-C₃-alkyl)-N(R⁹)(R¹⁰) group and C₃-C₆-cycloalkyl group, or R⁷ and R⁸ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 6-membered heterocycloalkyl group, wherein said 4- to 6-membered nitrogen containing heterocycloalkyl group is optionally substituted with a group selected from C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl) and —C(═O)O(C₁-C₄-alkyl), R⁹ and R¹⁰ represent, identically or differently, a hydrogen atom or a C₁-C₃-alkyl group, or R⁹ and R¹⁰ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 6-membered heterocycloalkyl group, R¹¹ represents a hydrogen atom or a group selected from a cyano group and a —C(═O)(C₁-C₃-haloalkyl) group, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxid thereof.
 4. The method according to claim 1, wherein R¹ represents a group selected from a C₅-C₈-alkyl group, a C₄-C₈-cycloalkyl group, which is optionally substituted, one or two times, with a phenyl group, wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom, a C₁-C₃-alkyl group which is substituted with a C₃-C₆-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a hydroxy group or a phenyl group, a C₃-C₆-alkyl group which is substituted with a monocyclic or bicyclic heteroaryl group, a —(C₃-C₆-alkyl)-N(R⁷)(R⁸) group, a —(C₃-C₆-alkyl)-C(═O)N(R⁷)(R⁸) group, a 4- to 6-membered heterocycloalkyl group, which is optionally substituted one or two times, each substituent independently selected from a C₁-C₃-alkyl group, and which is connected to the rest of the molecule via a carbon atom of the said heterocycloalkyl group, a phenyl group, which is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from C₁-C₄-alkyl, C₁-C₃-haloalkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂(C₁-C₃-alkyl), —S(═O)(═NR¹¹)(C₁-C₃-alkyl) and —P(═O)(C₁-C₃-alkyl)₂, an indanyl group and a monocyclic- or bicyclic heteroaryl group, which are optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy, R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from a C₁-C₆-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₂-C₆-alkenyl group, and a phenyl group, wherein said C₁-C₆-alkyl group is optionally substituted with a C₃-C₆-cycloalkyl group or a NR⁷R⁸ group R⁴ represents a group selected from a C₂-C₆-alkenyl group, a C₃-C₆-cycloalkyl group, a C₂-C₆-hydroxyalkyl group, and a C₁-C₆-alkyl group, which is optionally substituted with a group selected from C₃-C₆-cycloalkyl and phenyl, R⁵ represents a halogen atom or a group selected from a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₆-hydroxyalkyl group, a (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)- group, a C₁-C₆-alkoxy group, C₁-C₆-alkylsulfanyl group, —(C₁-C₆-alkyl)-N(R⁷)(R⁸) group, a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group R⁶ represents a hydrogen atom or a C₁-C₄-alkyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a C₁-C₃-alkyl group or a cyclopropyl group, and R¹¹ represents a hydrogen atom, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 5. The method according to claim 1, wherein R¹ represents a group selected from a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group, a C₁-C₂-alkyl group which is substituted with a C₅-C₇-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a phenyl group, a C₂-C₅-hydroxyalkyl group, a —(C₃-C₅-alkyl)-N(R⁷)(R⁸) group, a —(C₃-C₅-alkyl)-C(═O)N(R⁷)(R⁸) group, a 5- to 6-membered heterocycloalkyl group, which is optionally substituted one or two times, with a C₁-C₃-alkyl group, and which is connected to the rest of the molecule via a carbon atom, a phenyl group, which is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —(C₁-C₃-alkyl)-N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and an indanyl group, and a monocyclic heteroaryl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy, R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₆-haloalkyl group, a C₂-C₆-alkenyl group and a phenyl group, wherein said C₁-C₆-alkyl group is optionally substituted with a cyclopropyl group or a NR⁷R⁸ group, R⁴ represents a group selected from a C₂-C₄-alkenyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-hydroxyalkyl group, and a C₁-C₅-alkyl group, which is optionally substituted with a group selected from cyclopropyl and phenyl, R⁵ represents a halogen atom or a group selected from a C₁-C₄-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₃-hydroxyalkyl group, (C₁-C₃-alkyl)-O—(C₁-C₃-alkyl)- group, a C₁-C₄-alkoxy group, a C₁-C₃-alkylsulfanyl group, a —(C₁-C₃-alkyl)-N(R⁷)(R⁸) group, a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group R⁶ represents a hydrogen atom or a C₁-C₃-alkyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a C₁-C₃-alkyl group or a cyclopropyl group, R¹¹ represents a hydrogen atom, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 6. The method according to claim 1, wherein R¹ represents a group selected from a C₅-C₇-alkyl group, a C₅-C₇-cycloalkyl group, a C₁-C₂-alkyl group which is substituted with a C₅-C₆-cycloalkyl group, a C₂-C₆-alkyl group which is substituted with a phenyl group, a C₃-C₄-hydroxyalkyl group, a —(C₃-C₄-alkyl)-N(R⁷)(R⁸) group, a CH₃CH₂CH—C(═O)NH₂ group, a 5- to 6-membered heterocycloalkyl group, which is optionally substituted one or two times, with a C₁-C₃-alkyl group, and which is connected to the rest of the molecule via a carbon atom, a phenyl group, which is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, hydroxy, —C(═O)OR⁶, —C(═O)N(R⁷)(R⁸), —N(R⁷)(R⁸), —O—C(═O)—(C₁-C₄-alkyl), —S—C₁-C₃-alkyl, —S(═O)₂—C₁-C₃-alkyl, —S(═O)(═NH)(C₁-C₃-alkyl) and —(C₁-C₃-alkyl)-N(R⁷)(R⁸), an indanyl group, and a monocyclic heteroaryl group, which is optionally substituted one or two times, each substituent independently selected from a group selected from C₁-C₃-alkyl and C₁-C₃-alkoxy, R² represents a hydrogen atom or a halogen atom, R³ represents a group selected from a C₁-C₆-alkyl group, a C₃-C₆-cycloalkyl group, a C₁-C₃-haloalkyl group, a C₂-C₆-alkenyl group and a phenyl group, wherein said C₁-C₆-alkyl group is optionally substituted with a cyclopropyl group or a N(R⁷)(R⁸) group, R⁴ represents a group selected from a C₂-C₄-alkenyl group, a C₃-C₈-cycloalkyl group, a C₁-C₃-hydroxyalkyl group, a C₁-C₄-alkyl group, which is optionally substituted with a group selected from cyclopropyl and phenyl, R⁵ represents a halogen atom or a group selected from a C₁-C₄-alkyl group, a C₃-C₈-cycloalkyl group, a C₁-C₃-haloalkyl group, which is optionally substituted with a hydroxy group, a C₁-C₃-hydroxyalkyl group, a CH₃O—(C₁-C₂-alkyl)- group, a C₁-C₃-alkoxy group, a methylsulfanyl group, a —(C₁-C₂-alkyl)-N(R⁷)(R⁸) group, a —N(R⁷)(R⁸) group, a —C(═O)OR⁶ group, a —C(═O)N(R⁷)(R⁸) group, and a —S(═O)(═NR¹¹)(C₁-C₃-alkyl) group R⁶ represents a hydrogen atom or a methyl group, R⁷ and R⁸ represent, independently for each occurrence, a hydrogen atom or a C₁-C₃-alkyl group or a cyclopropyl group, R¹¹ represents a hydrogen atom, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 7. The method according to claim 1, wherein R¹ represents a group selected from 3-pentyl, 2,2-dimethylpropyl, 4-heptyl, 4-fluorophenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclohexylethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl, 1-hydroxybutan-2-yl, 1-cyanobutan-2-yl, 1-phenylbutan-2-yl, 1-amino-2-propyl, 1-amino-2-butyl, 1-amino-1-oxobutan-2-yl, indan-2-yl, a 5- to 6-membered heterocycloalkyl group, which is selected from tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl and piperidin-4-yl, and which is optionally substituted one or two times with a methyl group, a phenyl group, which is optionally substituted, one, two or three times, each substituent independently selected from a fluorine atom or a chlorine atom or a group selected from methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, —O—C(═O)-1,1-dimethylethyl, hydroxy, —C(═O)OCH₃, —C(═O)NH-cyclopropyl, amino, methylamino, aminomethyl, —S—CH₃, —S(═O)₂CH₃, and —S(═O)(NH)CH₃, and a monocyclic heteroaryl group, which is selected from oxazol-2-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, chinolin-5-yl, indazol-5-yl, and which is optionally substituted one or two times, each substituent independently selected from methyl and methoxy, R² represents a hydrogen atom or a fluorine or chlorine atom, R³ represents a group selected from propyl, 2-methylpropyl, 3-pentyl, cyclopropylmethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, N,N-dimethylaminoethyl, and phenyl, R⁴ represents a group selected from methyl, ethyl, propyl, isopropyl, 2-butyl, prop-2-en-1-yl, cyclopropylmethyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxyethyl, R⁵ represents a chlorine atom or a group selected from methyl, ethyl, propyl, isopropyl, 2-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 1-chloroethyl, 1-hydroxy-2,2,2-trifluoroethyl, 1-methoxyethyl, methoxy, isopropoxy, methylsulfanyl, aminomethyl, (methylamino)methyl, (dimethylamino)methyl, 1-aminoethyl, 2-aminoethyl, methylamino and ethyl(methyl)amino, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHcyclopropyl, —C(═O)N(CH₃)₂, and —S(═O)(═NH)CH₃, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 8. The method according to claim 1, wherein the compound is selected from the group consisting of: 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenyl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]benzamide, 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(1S)-1-phenylethoxy]-N-[3-(trifluoromethyl)phenyl]benzamide, 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-[(1S)-1-phenylethoxy]benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide, 5-fluoro-N-(2-fluorophenyl)-4-[3-methyl-5-oxo-4-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[3-(trifluoromethyl)phenyl]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(trifluoromethyl)phenyl]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(trifluoromethyl)phenyl]benzamide, N-(3-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-(2-cyano-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, N-(2,2-dimethylpropyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-cycloheptyl-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-hydroxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, N-(cyclohexylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-(1-cyclohexylethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, Mixture of Stereoisomers, N-(2,4-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[2-(methylamino)phenyl]-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(3-methoxyphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[2-(propan-2-yl)phenyl]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-(2-propylphenyl)benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-ethylphenyl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]-N-[4-(propan-2-yl)phenyl]benzamide, N-(2,3-dihydro-1H-inden-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-(cyclopentylmethyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, N-(4-amino-2,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-(2-amino-4,6-dimethylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-[4-(aminomethyl)-3-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pentan-2-yloxy)benzamide, 4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopropyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclobutyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopropyl-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihyro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluorophenyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-[(1S)-1-phenylethoxy]benzamide, N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluorophenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-fluoro-2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, N-[(2R)-1-amino-1-oxobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-N-(heptan-4-yl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 2-(1-cyclohexylethoxy)-N-(2,4-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide, mixture of stereoisomers, N-(2-amino-6-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide, mixture of stereoisomers, N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide, mixture of stereoisomers, 2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide, mixture of stereoisomers, 5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide, mixture of stereoisomers, N-(2-amino-6-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-(pent-4-en-2-yloxy)benzamide, mixture of stereoisomers, N-(2,6-dimethylphenyl)-5-fluoro-4-{3-[(1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2R)-pentan-2-yloxy]benzamide, mixture of stereoisomers, N-(4-amino-2-methylphenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[pent-4-en-2-yloxy]benzamide, mixture of stereoisomers, 5-fluoro-4-{4-methyl-3-[(methylamino)methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, 2-(1-cyclohexylethoxy)-N-(2,6-dimethylphenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide, mixture of stereoisomers, 4-[3-(aminomethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methylphenyl)-2-[(2S)-pentan-2-yloxy]benzamide, N-[4-amino-2-(trifluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, N-[2-(aminomethyl)-6-methylphenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(2S)-pentan-2-yloxy]benzamide, 4-{3-[(1R)-1-aminoethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(4-amino-2-methylphenyl)-2-(1-cyclohexylethoxy)-5-fluorobenzamide, mixture of stereoisomers, 4-(4-cyclopentyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-{3-[ethyl(methyl)amino]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, single stereomer, N-(2,6-difluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-{3-[(dimethylamino)methyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-(4-methyl-5-oxo-3-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-[3-(2-aminoethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[4-methyl-3-(methylamino)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-tert-butyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-chloro-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-[4-(cyclopropylmethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-(3-methyl-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-[3-ethyl-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3,4-diethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-cyclopropyl-3-methoxy-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-chloro-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(3-cyclopentyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-[4-(butan-2-yl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, mixture of stereoisomers, 4-[3-(butan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, mixture of stereoisomers, N-(2,6-difluorophenyl)-4-[4-ethyl-3-(methylsulfanyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-5-fluoro-4-[3-(1-methoxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, mixture of stereoisomers, N-(2,6-difluorophenyl)-4-[4-ethyl-5-oxo-3-(propan-2-yloxy)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-(4-benzyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2,6-difluorophenyl)-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-N-(2-fluoro-6-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-dichlorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-dichlorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-dichlorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-{3-[(1S)-1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-N-(2-fluoro-6-methylphenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, 5-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, N-(2,6-difluorophenyl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(tetrahydrofuran-3-yl)benzamide, mixture of stereoisomers, 5-fluoro-N-[(2R)-1-hydroxypropan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1H-pyrazol-3-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-2-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyridin-4-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1-methylpiperidin-4-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(tetrahydro-2H-pyran-4-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyrimidin-4-yl)benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(1,3-oxazol-2-yl)benzamide, 5-fluoro-N-[(2R)-1-hydroxybutan-2-yl]-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, N-cyclopentyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, N-cyclohexyl-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, 5-fluoro-N-(2-hydroxypropyl)-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, mixture of stereoisomers, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-phenylbenzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(pyrimidin-2-yl)benzamide, N-[(2R)-1-aminopropan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, N-[(2R)-1-aminobutan-2-yl]-5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}benzamide, 5-fluoro-4-[4-methyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-4-methylpentan-2-yl]oxy}-N-(piperidin-4-yl)benzamide, 2-(1-cyclohexylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 2-[(1-cyclopropylpropan-2-yl)oxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 2-(1-cyclopentylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 2-(1-cyclopropylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(1-phenylethoxy)benzamide, mixture of stereoisomers, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-[(3-ethylpentan-2-yl)oxy]-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(4-methylpent-3-en-2-yl)oxy]-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)-2-(pent-4-en-2-yloxy)benzamide, mixture of stereoisomers, 2-(1-cyclobutylethoxy)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(pentan-3-yl)benzamide, mixture of stereoisomers, 5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(pentan-3-yl)-2-[(2S)-pentan-2-yloxy]benzamide, mixture of stereoisomers, and 5-fluoro-4-[3-(1-hydroxyethyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methylphenyl)-2-(pentan-2-yloxy)benzamide, mixture of stereoisomers, N-(2-chloro-6-fluorophenyl)-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2,6-difluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide (Racemic) N-(2-chloro-6-fluorophenyl)-2-{[1,1-difluoropropan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzamide (Racemic) N-(2-chloro-6-fluorophenyl)-4-[4-cyclopropyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-4-[4-cyclobutyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-2-{[3,3-difluorobutan-2-yl]oxy}-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluorobenzamide (Racemic), 5-fluoro-4-[3-(hydroxymethyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-3-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide N-(2-chloro-6-fluorophenyl)-3-fluoro-4-[3-(2-hydroxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide N-(6-chloro-2-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide N-(6-chloro-2-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 3-chloro-4-(4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamido)-5-fluorophenyl 2,2-dimethylpropanoate, N-(2-chloro-6-fluoro-4-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluoro-3-methoxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, N-(2-chloro-6-fluoro-3-hydroxyphenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, 2-[(1S)-1-cyclohexylethoxy]-N-(1,4-dimethyl-1H-pyrazol-3-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluorobenzamide, 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[1-(4-fluorophenyl)cyclopropyl]benzamide 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(oxan-4-yl)benzamide 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-phenylbutan-2-yl)benzamide 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[3-(methanesulfonyl)phenyl]benzamide, 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(1-methyl-1H-pyrazol-5-yl)benzamide, 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(methylsulfanyl)phenyl]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(4-methylpyridin-3-yl)-2-[(1S)-1-phenylethoxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-methylquinolin-5-yl)-2-[(1S)-1-phenylethoxy]benzamide, N-[3-(cyclopropylcarbamoyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide, N-[2-(difluoromethyl)phenyl]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide, 4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(6-methyl-1H-indazol-5-yl)-2-[(1S)-1-phenylethoxy]benzamide, N-(1-cyanobutan-2-yl)-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-[(1S)-1-phenylethoxy]benzamide, 2-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-(2-fluoro-6-methylphenyl)benzamide, 2-[(1S)-1-cyclohexylethoxy]-4-(3-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-N-[4-(S-methanesulfonimidoyl)phenyl]benzamide (mixture of stereoisomers), N-(2,6-difluorophenyl)-4-[4-ethyl-3-(S-methanesulfonimidoyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide (Mixture of stereoisomers), 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2,6-difluorophenyl)carbamoyl]-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 4-ethyl-1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2,6-dichlorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-3-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-3-{[1,1-difluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid (Racemic), 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(2-fluoro-4-[(2-fluoro-6-methylphenyl)carbamoyl]-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-propyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-5-{[3,3-difluorobutan-2-yl]oxy}-2-fluorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid (racemic), 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-5-oxo-4-(prop-2-en-1-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-cyclobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid, 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, 1-(4-[(2-chloro-6-fluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, N-cyclopropyl-1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-N,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide 1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-N,N-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide Methyl-1-(4-[(2,6-difluorophenyl)carbamoyl]-2-fluoro-5-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylate, 5-fluoro-4-{3-[1-hydroxyethyl]-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(2-methylphenyl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide (Mixture of stereoisomers) and 4-{4-ethyl-5-oxo-3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-5-fluoro-N-(2-methoxy-4-methylpyridin-3-yl)-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide (mixture of stereoisomers) or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 9. The method according to claim 1, wherein said compound is N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide; or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.
 10. The method according to claim 1, wherein the hyperproliferative disease is cancer.
 11. The method according to claim 10, wherein the cancer is selected from acute myeloid leukemia, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, leukemia, lung cancer, lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, and sarcoma.
 12. The method according to claim 10, wherein the cancer is lymphoma selected from the group of AIDS-related lymphoma, chronic lymphocyctic lymphoma (CLL), non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL, anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, hair cell lymphoma, Hodgkin's disease, mantel cell lymphoma (MCL), lymphoma of the central nervous system, small lymphocytic lymphoma, and chronic lymphocytic lymphoma.
 13. The method according to claim 12, wherein the cancer is a subtype of NHL selected from Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, and double-expressor lymphoma.
 14. The method according to claim 1, wherein the hyperproliferative disease is selected from psoriasis keloids; hyperplasias affecting the skin; benign prostate hyperplasia (BPH); solid tumors; cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases; sarcomas; hematological malignancies; leukemias; lymphomas; and multiple myelomas.
 15. The method according to claim 1, wherein the hyperproliferative disease is lung cancer.
 16. The method according to claim 15, wherein said lung cancer is small cell lung carcinoma.
 17. The method according to claim 15, wherein said lung cancer is non-small cell lung carcinoma.
 18. The method according to claim 1, wherein said hyperproliferative disease is leukemia.
 19. The method according to claim 1, wherein the hyperproliferative disease is myelodysplastic syndrome or leukemia selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, promyelocytic leukemia, bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, and plasma cell leukemia. 